ORCID Profile
0000-0001-5132-0774
Current Organisation
Walter and Eliza Hall Institute of Medical Research
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Genetics | Neurogenetics | Neurocognitive Patterns and Neural Networks | Central Nervous System | Neurogenetics | Gene Expression | Neurology And Neuromuscular Diseases | Genetic Immunology | Neurosciences | Diagnostic Applications | Bioinformatics | Quantitative Genetics (incl. Disease and Trait Mapping Genetics)
ANZSRC Socio-Economic Objective (SEO)
Inherited Diseases (incl. Gene Therapy) | Disease distribution and transmission | Infectious diseases | Nervous System and Disorders | Nervous system and disorders | Diagnostics | Treatments (e.g. chemicals, antibiotics) | Hearing, Vision, Speech and Their Disorders | Expanding Knowledge in the Medical and Health Sciences |
Related Links
Publications
Infanticide vs. inherited cardiac arrhythmias
Publisher: Oxford University Press (OUP)
Date: 17-11-2021
Abstract: In 2003, an Australian woman was convicted by a jury of smothering and killing her four children over a 10-year period. Each child died suddenly and unexpectedly during a sleep period, at ages ranging from 19 days to 18 months. In 2019 we were asked to investigate if a genetic cause could explain the children’s deaths as part of an inquiry into the mother’s convictions. Whole genomes or exomes of the mother and her four children were sequenced. Functional analysis of a novel CALM2 variant was performed by measuring Ca2+-binding affinity, interaction with calcium channels and channel function. We found two children had a novel calmodulin variant (CALM2 G114R) that was inherited maternally. Three genes (CALM1-3) encode identical calmodulin proteins. A variant in the corresponding residue of CALM3 (G114W) was recently reported in a child who died suddenly at age 4 and a sibling who suffered a cardiac arrest at age 5. We show that CALM2 G114R impairs calmodulin's ability to bind calcium and regulate two pivotal calcium channels (CaV1.2 and RyR2) involved in cardiac excitation contraction coupling. The deleterious effects of G114R are similar to those produced by G114W and N98S, which are considered arrhythmogenic and cause sudden cardiac death in children. A novel functional calmodulin variant (G114R) predicted to cause idiopathic ventricular fibrillation, catecholaminergic polymorphic ventricular tachycardia, or mild long QT syndrome was present in two children. A fatal arrhythmic event may have been triggered by their intercurrent infections. Thus, calmodulinopathy emerges as a reasonable explanation for a natural cause of their deaths.
A focal epilepsy and intellectual disability syndrome is due to a mutation in TBC1D24
Publisher: Elsevier BV
Date: 09-2010
Familial adult myoclonic epilepsy type 1 SAMD12 TTTCA repeat expansion arose 17,000 years ago and is present in Sri Lankan and Indian families
Publisher: Springer Science and Business Media LLC
Date: 16-03-2202
Inhibition of Upf2-Dependent Nonsense-Mediated Decay Leads to Behavioral and Neurophysiological Abnormalities by Activating the Immune Response
Publisher: Elsevier BV
Date: 11-2019
NEK1 and STMN2 short tandem repeat lengths are not associated with Australian amyotrophic lateral sclerosis risk
Publisher: Elsevier BV
Date: 08-2022
DOI: 10.1016/J.NEUROBIOLAGING.2022.04.012
Abstract: Sporadic amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a complex genetic architecture. The lengths of two short tandem repeats (STRs), at the NEK1 and STMN2 loci, were recently associated with ALS risk in cohorts of European descent. The STMN2 STR was proposed to be predictive of clinical features including the age of onset and disease duration in bulbar onset cases. We sought to investigate NEK1 and STMN2 STR lengths in a cohort of Australian sporadic ALS cases (n = 608) and neurologically healthy controls (n = 4689) of European ancestry. ExpansionHunter was used to determine NEK1 and STMN2 STR length genotypes from whole-genome sequencing data followed by PCR validation of predicted lengths. No significant association was identified between sporadic ALS risk and the length of either STR. Further, neither NEK1 nor STMN2 STR lengths were indicative of the age of onset or disease duration. We report that the NEK1 and STMN2 STRs were not associated with ALS risk or clinical features in this Australian sporadic ALS cohort.
The –590C/T and –34C/T interleukin-4 promoter polymorphisms are not associated with atopic eczema in childhood
Publisher: Elsevier BV
Date: 08-2001
Abstract: Susceptibility to the development of asthma and other atopic diseases is known to have a genetic component. To date, several studies have linked chromosome 5q31 to asthma and atopy in human beings. This region harbors a cluster of cytokine and growth factor genes, IL-4 presenting as a prime atopy candidate gene, inasmuch as it plays a pivotal role in the atopy pathway. Our approach was to identify polymorphisms within the promoter regions of IL-4 and test their association with atopic eczema. Polymorphisms were typed in a cohort of 76 small nuclear families and 25 triads with childhood atopic eczema. The genotypes were used to test for linkage in the presence of association with atopic eczema. A new polymorphism, -34C/T, was identified and studied with a known polymorphism, -590C/T. On its own, each polymorphism showed no association with atopic eczema. The 2 polymorphisms were used to generate haplotypes, and a significant result was found for the -590C/-34C haplotype. However, after Bonferroni correction for multiple testing, the association became nonsignificant. Neither polymorphism predisposes to early-onset atopic eczema by itself, but suggestive linkage was found for the -590C/-34C haplotype in this study.
An ethyl-nitrosourea-induced point mutation in Phex causes exon skipping, X-linked hypophosphatemia, and rickets
Publisher: Elsevier BV
Date: 11-2002
Iron homeostasis governs erythroid phenotype in Polycythemia Vera
Publisher: Cold Spring Harbor Laboratory
Date: 04-05-2022
DOI: 10.1101/2022.05.03.490556
Abstract: Polycythemia Vera (PV) is a myeloproliferative neoplasm driven by activating mutations in JAK2 that result in unrestrained erythrocyte production, increasing patients’ hematocrit and hemoglobin concentration, placing them at risk of life-threatening thrombotic events. Our GWAS of 440 PV cases and 403,351 controls utilising UK Biobank data found that SNPs in HFE known to cause hemochromatosis are highly associated with PV diagnosis, linking iron regulation to PV. Analysis of the FinnGen dataset independently confirmed over-representation of homozygous HFE mutations in PV patients. HFE influences expression of hepcidin, the master regulator of systemic iron homeostasis. Through genetic dissection of PV mouse models, we show that the PV erythroid phenotype is directly linked to hepcidin expression: endogenous hepcidin upregulation alleviates erythroid disease whereas hepcidin ablation worsens it. Further, we demonstrate that in PV, hepcidin is not regulated by expanded erythropoiesis but is likely governed by inflammatory cytokines signalling via GP130 coupled receptors. These findings have important implications for understanding the pathophysiology of PV and offer new therapeutic strategies for this disease.
Correction: Genetic aetiologies for childhood speech disorder: novel pathways co-expressed during brain development (Molecular Psychiatry, (2023), 28, 4, (1647-1663), 10.1038/s41380-022-01764-8)
Publisher: Springer Science and Business Media LLC
Date: 19-01-2202
A cross-platform approach identifies genetic regulators of human metabolism and health
Publisher: Springer Science and Business Media LLC
Date: 2021
Polycomb repressive complex 2 (PRC2) restricts hematopoietic stem cell activity
Publisher: Public Library of Science (PLoS)
Date: 15-04-2008
Dorsal language stream anomalies in an inherited speech disorder
Publisher: Oxford University Press (OUP)
Date: 23-02-2019
DOI: 10.1093/BRAIN/AWZ018
Abstract: Speech disorders are highly prevalent in the preschool years, but frequently resolve. The neurobiological basis of the most persistent and severe form, apraxia of speech, remains elusive. Current neuroanatomical models of speech processing in adults propose two parallel streams. The dorsal stream is involved in sound to motor speech transformations, while the ventral stream supports sound/letter to meaning. Data-driven theories on the role of these streams during atypical speech and language development are lacking. Here we provide comprehensive behavioural and neuroimaging data on a large novel family where one parent and 11 children presented with features of childhood apraxia of speech (the same speech disorder associated with FOXP2 variants). The genetic cause of the disorder in this family remains to be identified. Importantly, in this family the speech disorder is not systematically associated with language or literacy impairment. Brain MRI scanning in seven children revealed large grey matter reductions over the left temporoparietal region, but not in the basal ganglia, relative to typically-developing matched peers. In addition, we detected white matter reductions in the arcuate fasciculus (dorsal language stream) bilaterally, but not in the inferior fronto-occipital fasciculus (ventral language stream) nor in primary motor pathways. Our findings identify disruption of the dorsal language stream as a novel neural phenotype of developmental speech disorders, distinct from that reported in speech disorders associated with FOXP2 variants. Overall, our data confirm the early role of this stream in auditory-to-articulation transformations. 10.1093/brain/awz018_video1 awz018media1 6018582401001.
Detecting Tandem Repeat Expansions Using Short-Read Sequencing for Clinical Use
Publisher: Springer US
Date: 2022
The advantages of dense marker sets for linkage analysis with very large families
Publisher: Springer Science and Business Media LLC
Date: 25-01-2007
DOI: 10.1007/S00439-007-0323-5
Abstract: Dense sets of hundreds of thousands of markers have been developed for genome-wide association studies. These marker sets are also beneficial for linkage analysis of large, deep pedigrees containing distantly related cases. It is impossible to analyse jointly all genotypes in large pedigrees using the Lander-Green Algorithm, however, as marker density increases it becomes less crucial to analyse all in iduals' genotypes simultaneously. In this report, an approximate multipoint non-parametric technique is described, where large pedigrees are split into many small pedigrees, each containing just two cases. This technique is demonstrated, using phased data from the International Hapmap Project to simulate sets of 10,000, 50,000 and 250,000 markers, showing that it becomes increasingly accurate as more markers are genotyped. This method allows routine linkage analysis of large families with dense marker sets and represents a more easily applied alternative to Monte Carlo Markov Chain methods.
A missense mutation in the MLKL brace region promotes lethal neonatal inflammation and hematopoietic dysfunction
Publisher: Springer Science and Business Media LLC
Date: 19-06-2020
DOI: 10.1038/S41467-020-16819-Z
Abstract: MLKL is the essential effector of necroptosis, a form of programmed lytic cell death. We have isolated a mouse strain with a single missense mutation, Mlkl D139V , that alters the two-helix ‘brace’ that connects the killer four-helix bundle and regulatory pseudokinase domains. This confers constitutive, RIPK3 independent killing activity to MLKL. Homozygous mutant mice develop lethal postnatal inflammation of the salivary glands and mediastinum. The normal embryonic development of Mlkl D139V homozygotes until birth, and the absence of any overt phenotype in heterozygotes provides important in vivo precedent for the capacity of cells to clear activated MLKL. These observations offer an important insight into the potential disease-modulating roles of three common human MLKL polymorphisms that encode amino acid substitutions within or adjacent to the brace region. Compound heterozygosity of these variants is found at up to 12-fold the expected frequency in patients that suffer from a pediatric autoinflammatory disease, chronic recurrent multifocal osteomyelitis (CRMO).
Unexpected diagnosis of myotonic dystrophy type 2 repeat expansion by genome sequencing
Publisher: Springer Science and Business Media LLC
Date: 09-08-2023
DOI: 10.1038/S41431-022-01166-Y
Abstract: Several neurological disorders, such as myotonic dystrophy are caused by expansions of short tandem repeats (STRs) which can be difficult to detect by molecular tools. Methodological advances have made repeat expansion (RE) detection with whole genome sequencing (WGS) feasible. We recruited a multi-generational family (family A) ascertained for genetic studies of autism spectrum disorder. WGS was performed on seven children from four nuclear families from family A and analyzed for REs of STRs known to cause neurological disorders. We detected an expansion of a heterozygous intronic CCTG STR in CNBP in two siblings. This STR causes myotonic dystrophy type 2 (DM2). The expansion did not segregate with the ASD phenotype. Repeat-primed PCR showed that the DM2 CCTG motif was expanded above the pathogenic threshold in both children and their mother. On subsequent examination, the mother had mild features of DM2. We show that screening of STRs in WGS datasets has diagnostic utility, both in the clinical and research domain, with potential management and genetic counseling implications.
Identification of a novel RNF213 variant in a family with heterogeneous intracerebral vasculopathy
Publisher: SAGE Publications
Date: 17-07-2014
DOI: 10.1111/IJS.12306
Progressive Myoclonus Epilepsies Diagnostic Yield with Next-Generation Sequencing in Previously Unsolved Cases
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-11-2021
DOI: 10.1212/NXG.0000000000000641
Abstract: To assess the current diagnostic yield of genetic testing for the progressive myoclonus epilepsies (PMEs) of an Italian series described in 2014 where Unverricht-Lundborg and Lafora diseases accounted for ∼50% of the cohort. Of 47/165 unrelated patients with PME of indeterminate genetic origin, 38 underwent new molecular evaluations. Various next-generation sequencing (NGS) techniques were applied including gene panel analysis (n = 7) and/or whole-exome sequencing (WES) (WES singleton n = 29, WES trio n = 7, and WES sibling n = 4). In 1 family, homozygosity mapping was followed by targeted NGS. Clinically, the patients were grouped in 4 phenotypic categories: “Unverricht-Lundborg disease-like PME,” “late-onset PME,” “PME plus developmental delay,” and “PME plus dementia.” Sixteen of 38 (42%) unrelated patients reached a positive diagnosis, increasing the overall proportion of solved families in the total series from 72% to 82%. Likely pathogenic variants were identified in NEU1 (2 families), CERS1 (1 family), and in 13 nonfamilial patients in KCNC1 (3), DHDDS (3), SACS , CACNA2D2 , STUB1 , AFG3L2 , CLN6 , NAXE , and CHD2 . Across the different phenotypic categories, the diagnostic rate was similar, and the same gene could be found in different phenotypic categories. The application of NGS technology to unsolved patients with PME has revealed a collection of very rare genetic causes. Pathogenic variants were detected in both established PME genes and in genes not previously associated with PME, but with progressive ataxia or with developmental encephalopathies. With a diagnostic yield %, PME is one of the best genetically defined epilepsy syndromes.
Development of plasmacytoid and conventional dendritic cell subtypes from single precursor cells derived in vitro and in vivo
Publisher: Springer Science and Business Media LLC
Date: 07-10-2007
DOI: 10.1038/NI1522
Abstract: The development of functionally specialized subtypes of dendritic cells (DCs) can be modeled through the culture of bone marrow with the ligand for the cytokine receptor Flt3. Such cultures produce DCs resembling spleen plasmacytoid DCs (pDCs), CD8(+) conventional DCs (cDCs) and CD8(-) cDCs. Here we isolated two sequential DC-committed precursor cells from such cultures: iding 'pro-DCs', which gave rise to transitional 'pre-DCs' en route to differentiating into the three distinct DC subtypes (pDCs, CD8(+) cDCs and CD8(-) cDCs). We also isolated an in vivo equivalent of the DC-committed pro-DC precursor cell, which also gave rise to the three DC subtypes. Clonal analysis of the progeny of in idual pro-DC precursors demonstrated that some pro-DC precursors gave rise to all three DC subtypes, some produced cDCs but not pDCs, and some were fully committed to a single DC subtype. Thus, commitment to particular DC subtypes begins mainly at this pro-DC stage.
Eukaryote-conserved methylarginine is absent in diplomonads and functionally compensated in Giardia
Publisher: Oxford University Press (OUP)
Date: 23-07-2020
Abstract: Methylation is a common posttranslational modification of arginine and lysine in eukaryotic proteins. Methylproteomes are best characterized for higher eukaryotes, where they are functionally expanded and evolved complex regulation. However, this is not the case for protist species evolved from the earliest eukaryotic lineages. Here, we integrated bioinformatic, proteomic, and drug-screening data sets to comprehensively explore the methylproteome of Giardia duodenalis—a deeply branching parasitic protist. We demonstrate that Giardia and related diplomonads lack arginine-methyltransferases and have remodeled conserved RGG/RG motifs targeted by these enzymes. We also provide experimental evidence for methylarginine absence in proteomes of Giardia but readily detect methyllysine. We bioinformatically infer 11 lysine-methyltransferases in Giardia, including highly erged Su(var)3-9, Enhancer-of-zeste and Trithorax proteins with reduced domain architectures, and novel annotations demonstrating conserved methyllysine regulation of eukaryotic elongation factor 1 alpha. Using mass spectrometry, we identify more than 200 methyllysine sites in Giardia, including in species-specific gene families involved in cytoskeletal regulation, enriched in coiled-coil features. Finally, we use known methylation inhibitors to show that methylation plays key roles in replication and cyst formation in this parasite. This study highlights reduced methylation enzymes, sites, and functions early in eukaryote evolution, including absent methylarginine networks in the Diplomonadida. These results challenge the view that arginine methylation is eukaryote conserved and demonstrate that functional compensation of methylarginine was possible preceding expansion and ersification of these key networks in higher eukaryotes.
ALPK3-deficient cardiomyocytes generated from patient-derived induced pluripotent stem cells and mutant human embryonic stem cells display abnormal calcium handling and establish that ALPK3 deficiency underlies familial cardiomyopathy
Publisher: Oxford University Press (OUP)
Date: 22-04-2016
Abstract: We identified a novel homozygous truncating mutation in the gene encoding alpha kinase 3 (ALPK3) in a family presenting with paediatric cardiomyopathy. A recent study identified biallelic truncating mutations of ALPK3 in three unrelated families therefore, there is strong genetic evidence that ALPK3 mutation causes cardiomyopathy. This study aimed to clarify the mutation mechanism and investigate the molecular and cellular pathogenesis underlying ALPK3-mediated cardiomyopathy. We performed detailed clinical and genetic analyses of a consanguineous family, identifying a new ALPK3 mutation (c.3792G>A, p.W1264X) which undergoes nonsense-mediated decay in ex vivo and in vivo tissues. Ultra-structural analysis of cardiomyocytes derived from patient-specific and human ESC-derived stem cell lines lacking ALPK3 revealed disordered sarcomeres and intercalated discs. Multi-electrode array analysis and calcium imaging demonstrated an extended field potential duration and abnormal calcium handling in mutant contractile cultures. This study validates the genetic evidence, suggesting that mutations in ALPK3 can cause familial cardiomyopathy and demonstrates loss of function as the underlying genetic mechanism. We show that ALPK3-deficient cardiomyocytes derived from pluripotent stem cell models recapitulate the ultrastructural and electrophysiological defects observed in vivo. Analysis of differentiated contractile cultures identified abnormal calcium handling as a potential feature of cardiomyocytes lacking ALPK3, providing functional insights into the molecular mechanisms underlying ALPK3-mediated cardiomyopathy.
A novel mutation in COCH-implications for genotype-phenotype correlations in DFNA9 hearing loss
Publisher: Wiley
Date: 02-11-2010
DOI: 10.1002/LARY.21159
Genome-wide meta-analysis of over 29,000 people with epilepsy reveals 26 loci and subtype-specific genetic architecture
Publisher: Cold Spring Harbor Laboratory
Date: 14-06-2022
DOI: 10.1101/2022.06.08.22276120
Abstract: Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here, we report a trans-ethnic GWAS including 29,944 cases, stratified into three broad- and seven sub-types of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants substantially close the missing heritability gap for GGE. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analysis of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current anti-seizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment.
High resolution imaging and five-year tuberculosis contact outcomes
Publisher: Cold Spring Harbor Laboratory
Date: 03-07-2023
DOI: 10.1101/2023.07.03.23292111
Abstract: The evolution of tuberculosis (TB) disease during the clinical latency period remains incompletely understood. 250 HIV-uninfected, adult household contacts of rif icin-resistant TB with a negative symptom screen underwent baseline 18 F-Fluorodeoxyglucose positron emission and computed tomography (PET/CT), repeated in 112 after 5-15 months. Following South African and WHO guidelines, participants did not receive preventive therapy. All participants had intensive baseline screening with spontaneous, followed by induced, sputum s ling and were then observed for an average of 4.7 years for culture-positive disease. Baseline PET/CT abnormalities were evaluated in relation to culture-positive disease. At baseline, 59 (23.6%) participants had lung PET/CT findings consistent with TB of which 29 (11.6%) were defined as Subclinical TB, and 30 (12%) Subclinical TB-inactive. A further 83 (33.2%) had other lung parenchymal abnormalities and 108 (43.2%) had normal lungs. Over 1107-person years of follow-up 14 cases of culture-positive TB were diagnosed. Six cases were detected by intensive baseline screening, all would have been missed by the South African symptom-based screening strategy and only one detected by a WHO-recommended chest X-Ray screening strategy. Those with baseline Subclinical TB lesions on PET/CT were significantly more likely to be diagnosed with culture-positive TB over the study period, compared to those with normal lung parenchyma (10/29 [34.5%] vs 2/108 [1.9%], Hazard Ratio 22.37 [4.89-102.47, p .001]). These findings challenge the latent/active TB paradigm demonstrating that subclinical disease exists up to 4 years prior to microbiological detection and/or symptom onset. There are important implications for screening and management of TB.
Recessive Spondylocarpotarsal Synostosis Syndrome Due to Compound Heterozygosity for Variants in MYH3
Publisher: Elsevier BV
Date: 06-2018
Iron homeostasis governs erythroid phenotype in polycythemia vera
Publisher: American Society of Hematology
Date: 16-03-2023
Abstract: Polycythemia Vera (PV) is a myeloproliferative neoplasm driven by activating mutations in JAK2 that result in unrestrained erythrocyte production, increasing patients' hematocrit and hemoglobin concentration, placing them at risk of life-threatening thrombotic events. Our GWAS of 440 PV cases and 403,351 controls utilizing UK Biobank data found that SNPs in HFE known to cause hemochromatosis are highly associated with PV diagnosis, linking iron regulation to PV. Analysis of the FinnGen dataset independently confirmed over-representation of homozygous HFE variants in PV patients. HFE influences the expression of hepcidin, the master regulator of systemic iron homeostasis. Through genetic dissection of PV mouse models, we show that the PV erythroid phenotype is directly linked to hepcidin expression: endogenous hepcidin upregulation alleviates erythroid disease whereas hepcidin ablation worsens it. Further, we demonstrate that in PV, hepcidin is not regulated by expanded erythropoiesis but is likely governed by inflammatory cytokines signaling via GP130 coupled receptors. These findings have important implications for understanding the pathophysiology of PV and offer new therapeutic strategies for this disease.
Genetic analysis of patients who experienced awareness with recall while under general anesthesia
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2019
DOI: 10.1097/ALN.0000000000002877
Abstract: Intraoperative awareness with recall while under apparently adequate general anesthesia is a rare, unexplained, and often very distressing phenomenon. It is possible that a relatively small number of genetic variants might underlie the failure of general anesthetic drugs to adequately suppress explicit memory formation and recall in the presence of apparently adequate anesthesia concentrations. The authors recruited 12 adult patients who had experienced an episode of intraoperative awareness with recall (compared with 12 controls), performed whole exome sequencing, and applied filtering to obtain a set of genetic variants that might be associated with intraoperative awareness with recall. The criteria were that the variant (1) had a minor allele frequency less than 0.1% in population databases, (2) was within exonic or splicing regions, (3) caused a nonsynonymous change, (4) was predicted to be functionally damaging, (5) was expressed in the top 50% of genes expressed in the brain, and (6) was within genes in Kyoto Encyclopedia of Genes and Genomes pathways associated with general anesthesia, drug metabolism, arousal, and memory. The authors identified 29 rare genetic variants in 27 genes that were absent in controls and could plausibly be associated with this disorder. One variant in CACNA1A was identified in two patients and two different variants were identified in both CACNA1A and CACNA1S. Of interest was the relative overrepresentation of variants in genes encoding calcium channels and purinergic receptors. Within the constraints of the filtering process used, the authors did not find any single gene variant or gene that was strongly associated with intraoperative awareness with recall. The authors report 27 candidate genes and associated pathways identified in this pilot project as targets of interest for future larger biologic and epidemiologic studies.
Myoclonic occipital photosensitive epilepsy with dystonia (MOPED): A familial epilepsy syndrome
Publisher: Elsevier BV
Date: 08-2015
DOI: 10.1016/J.EPLEPSYRES.2015.04.014
Abstract: To describe clinical and EEG phenotypes of a family with an unusual familial epilepsy syndrome characterized by myoclonus and dystonia. Family members underwent electroclinical phenotyping including review of EEGs and MRI. DNA from family members was genotyped using Illumina OmniExpress genotyping arrays. Parametric and nonparametric linkage analyses were performed using MERLIN. The disorder followed autosomal dominant (AD) inheritance and affected seven in iduals over two generations. Seizures began at a mean of 14.5 years. Six in iduals had spontaneous myoclonic seizures, of which five also had photic-induced myoclonus and four had photic-induced occipital seizures. Six in iduals had convulsive seizures generalized in two and focal in four. Photosensitivity was prominent with generalized spike wave and polyspike wave in four in iduals of which two also had occipital spikes. MRI scans were normal in the four in iduals tested. Extensive metabolic investigation was normal. Juvenile myoclonic epilepsy (JME) occurred in two and JME overlapping with idiopathic photosensitive epilepsy (IPOE) in four in iduals. All three affected males had a more severe disorder than the four affected females. Two males had a progressive neurological disorder with progressive myoclonus epilepsy and deterioration in their early 30s. They developed episodes of paroxysmal cervical dystonia with cognitive decline during periods of poor seizure control. One plateaued after years of poor seizure control but remained intractable with periods of deterioration. The other deteriorated with episodes of status dystonicus and status epilepticus, ataxia and a progressive ophthalmoplegia before succumbing at 38 years. Parametric linkage analysis identified three peaks achieving a maximum LOD score of 1.21. Nonparametric analysis identified eight peaks achieving LOD scores above 0.80. These were not statistically significant. This is a novel autosomal dominant familial epilepsy syndrome. "Myoclonic occipital photosensitive epilepsy with dystonia" (MOPED) involves a spectrum of phenotypes from JME, sometimes with an IPOE overlap, to progressive myoclonus epilepsy with paroxysmal dystonia.
Genomewide linkage study in 1,176 affected sister pair families identifies a significant susceptibility locus for endometriosis on chromosome 10q26
Publisher: Elsevier BV
Date: 09-2005
DOI: 10.1086/432960
XIBD: Software for inferring pairwise identity by descent on the X chromosome
Publisher: Oxford University Press (OUP)
Date: 21-03-2016
DOI: 10.1093/BIOINFORMATICS/BTW124
Abstract: Summary: XIBD performs pairwise relatedness mapping on the X chromosome using dense single nucleotide polymorphism (SNP) data from either SNP chips or next generation sequencing data. It correctly accounts for the difference in chromosomal numbers between males and females and estimates global relatedness as well as regions of the genome that are identical by descent (IBD). XIBD also generates novel graphical summaries of all pairwise IBD tracts for a cohort making it very useful for disease locus mapping. Availability and implementation: XIBD is written in R/Rcpp and executed from shell scripts that are freely available from bioinf.wehi.edu.au/software/XIBD along with accompanying reference datasets. Contact: henden.l@wehi.edu.au Supplementary information: Supplementary data are available at Bioinformatics online.
Genetic disruption of serine biosynthesis is a key driver of macular telangiectasia type 2 aetiology and progression
Publisher: Springer Science and Business Media LLC
Date: 09-03-2021
DOI: 10.1186/S13073-021-00848-4
Abstract: Macular telangiectasia type 2 (MacTel) is a rare, heritable and largely untreatable retinal disorder, often comorbid with diabetes. Genetic risk loci subtend retinal vascular calibre and glycine/serine/threonine metabolism genes. Serine deficiency may contribute to MacTel via neurotoxic deoxysphingolipid production however, an independent vascular contribution is also suspected. Here, we use statistical genetics to dissect the causal mechanisms underpinning this complex disease. We integrated genetic markers for MacTel, vascular and metabolic traits, and applied Mendelian randomisation and conditional and interaction genome-wide association analyses to discover the causal contributors to both disease and spatial retinal imaging sub-phenotypes. Genetically induced serine deficiency is the primary causal metabolic driver of disease occurrence and progression, with a lesser, but significant, causal contribution of type 2 diabetes genetic risk. Conversely, glycine, threonine and retinal vascular traits are unlikely to be causal for MacTel. Conditional regression analysis identified three novel disease loci independent of endogenous serine biosynthetic capacity. By aggregating spatial retinal phenotypes into endophenotypes, we demonstrate that SNPs constituting independent risk loci act via related endophenotypes. Follow-up studies after GWAS integrating publicly available data with deep phenotyping are still rare. Here, we describe such analysis, where we integrated retinal imaging data with MacTel and other traits genomics data to identify biochemical mechanisms likely causing this disorder. Our findings will aid in early diagnosis and accurate prognosis of MacTel and improve prospects for effective therapeutic intervention. Our integrative genetics approach also serves as a useful template for post-GWAS analyses in other disorders.
Familial epilepsy with anterior polymicrogyria as a presentation of COL18A1 mutations
Publisher: Elsevier BV
Date: 08-2017
DOI: 10.1016/J.EJMG.2017.06.002
Abstract: Knobloch syndrome [OMIM: (KNO1) #267750] is a rare and clinically heterogeneous autosomal recessive disorder caused by mutations in COL18A1. Knobloch syndrome is characterised by abnormalities of the eye and occipital skull defects however the full phenotypic spectrum is yet to be defined. This report describes a family of four affected sisters with polymicrogyria, refractory seizures, and intellectual impairment of varying severity with a Lennox-Gastaut phenotype, and complex eye abnormalities where a syndromic diagnosis was not initially made. Whole exome sequencing of two affected sisters followed by filtering for rare and potentially disease causing variants in all genes identified compound heterozygous variants in NM_030582.3 (COL18A1): c.3690G > A: p.(Trp1230*) and NM_030582.3 (COL18A1): c.4063_4064delCT: p.(Leu1355Valfs*72). The two variants co-segregated with the affected in iduals in the family. Identification of COL18A1 mutations in in iduals with a Lennox-Gastaut phenotype and anterior polymicrogyria but lacking the classical occipital encephalocele expands the COL18A1 clinical spectrum.
Germline and Mosaic Variants in PRKACA and PRKACB Cause a Multiple Congenital Malformation Syndrome
Publisher: Elsevier BV
Date: 11-2020
Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3
Publisher: Springer Science and Business Media LLC
Date: 29-10-2019
DOI: 10.1038/S41467-019-12763-9
Abstract: Familial Adult Myoclonic Epilepsy (FAME) is a genetically heterogeneous disorder characterized by cortical tremor and seizures. Intronic TTTTA/TTTCA repeat expansions in SAMD12 (FAME1) are the main cause of FAME in Asia. Using genome sequencing and repeat-primed PCR, we identify another site of this repeat expansion, in MARCH6 (FAME3) in four European families. Analysis of single DNA molecules with nanopore sequencing and molecular combing show that expansions range from 3.3 to 14 kb on average. However, we observe considerable variability in expansion length and structure, supporting the existence of multiple expansion configurations in blood cells and fibroblasts of the same in idual. Moreover, the largest expansions are associated with micro-rearrangements occurring near the expansion in 20% of cells. This study provides further evidence that FAME is caused by intronic TTTTA/TTTCA expansions in distinct genes and reveals that expansions exhibit an unexpectedly high somatic instability that can ultimately result in genomic rearrangements.
A survey of RNA editing at single-cell resolution links interneurons to schizophrenia and autism
Publisher: Cold Spring Harbor Laboratory
Date: 17-09-2021
Abstract: Conversion of adenosine to inosine in RNA by ADAR enzymes, termed “RNA editing,” is essential for healthy brain development. Editing is dysregulated in neuropsychiatric diseases, but has not yet been investigated at scale at the level of in idual neurons. We quantified RNA editing sites in nuclear transcriptomes of 3055 neurons from six cortical regions of a neurotypical female donor, and found 41,930 sites present in at least ten nuclei. Most sites were located within Alu repeats in introns or 3′ UTRs, and approximately 80% were cataloged in public RNA editing databases. We identified 9285 putative novel editing sites, 29% of which were also detectable in unrelated donors. Intersection with results from bulk RNA-seq studies provided cell-type and spatial context for 1730 sites that are differentially edited in schizophrenic brain donors, and 910 such sites in autistic donors. Autism-related genes were also enriched with editing sites predicted to modify RNA structure. Inhibitory neurons showed higher overall transcriptome editing than excitatory neurons, and the highest editing rates were observed in the frontal cortex. We used generalized linear models to identify differentially edited sites and genes between cell types. Twenty nine genes were preferentially edited in excitatory neurons, and 43 genes were edited more heavily in inhibitory neurons, including RBFOX1 , its target genes, and genes in the autism-associated Prader–Willi locus (15q11). The abundance of SNORD115/116 genes from locus 15q11 was positively associated with editing activity across the transcriptome. We contend that insufficient editing of autism-related genes in inhibitory neurons may contribute to the specific perturbation of those cells in autism.
ExpansionHunter Denovo: A computational method for locating known and novel repeat expansions in short-read sequencing data
Publisher: Cold Spring Harbor Laboratory
Date: 03-12-2019
DOI: 10.1101/863035
Abstract: Expansions of short tandem repeats are responsible for over 40 monogenic disorders, and undoubtedly many more pathogenic repeat expansions (REs) remain to be discovered. Existing methods for detecting REs in short-read sequencing data require predefined repeat catalogs. However recent discoveries have emphasized the need for detection methods that do not require candidate repeats to be specified in advance. To address this need, we introduce ExpansionHunter Denovo, an efficient catalog-free method for genome-wide detection of REs. Analysis of real and simulated data shows that our method can identify large expansions of 41 out of 44 pathogenic repeats, including nine recently reported non-reference REs not discoverable via existing methods. ExpansionHunter Denovo is freely available at github.com/Illumina/ExpansionHunterDenovo
A novel splice site mutation in the RDX gene causes DFNB24 hearing loss in an Iranian family
Publisher: Wiley
Date: 03-2009
DOI: 10.1002/AJMG.A.32670
Genome-Wide Linkage Analysis of the Acute Coronary Syndrome Suggests a Locus on Chromosome 2
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2002
DOI: 10.1161/01.ATV.0000016258.40568.F1
Abstract: A positive family history is a recognized cardiovascular risk factor, and genome-wide scans may reveal susceptibility loci for coronary artery disease. The acute coronary syndrome, consisting of myocardial infarction and unstable angina, is the most important manifestation of coronary disease and is characterized by atherosclerotic plaque disruption and coronary thrombosis. From ≈6000 hospital admissions to cardiology units, we identified affected sibling pairs (n=61) who had documented acute coronary syndrome before the age of 70 years. A 10-cM resolution genetic map and MAPMAKER/SIBS were used for genome-wide linkage analysis. One locus on chromosome 2q36-q37.3 showed linkage with a lod score of 2.63 ( P .0001). Separate multipoint fine-mapping of this locus with independent markers replicated the linkage results (lod 2.64). Two other regions on chromosomes 3q26-q27 and 20q11-q13 showed lod scores in excess of 1.5 ( P .005). This genome scan in acute coronary syndrome suggests 1 locus that encompasses the gene encoding the insulin receptor substrate-1 gene. Two other potential loci were identified. These data imply that a limited number of potent susceptibility genes exist for the acute coronary syndrome. Such genes are likely to be relevant to the combined processes of atherosclerosis, plaque instability, and coronary thrombosis.
Genome-wide genetic screen identifies host ubiquitination as important for Legionella pneumophila Dot/Icm effector translocation
Publisher: Hindawi Limited
Date: 08-06-2021
DOI: 10.1111/CMI.13368
Abstract: The Dot/Icm system of Legionella pneumophila is essential for virulence and delivers a large repertoire of effectors into infected host cells to create the Legionella containing vacuole. Since the secretion of effectors via the Dot/Icm system does not occur in the absence of host cells, we hypothesised that host factors actively participate in Dot/Icm effector translocation. Here we employed a high-throughput, genome-wide siRNA screen to systematically test the effect of silencing 18,120 human genes on translocation of the Dot/Icm effector, RalF, into HeLa cells. For the primary screen, we found that silencing of 119 genes led to increased translocation of RalF, while silencing of 321 genes resulted in decreased translocation. Following secondary screening, 70 genes were successfully validated as 'high confidence' targets. Gene set enrichment analysis of siRNAs leading to decreased RalF translocation, showed that ubiquitination was the most highly overrepresented category in the pathway analysis. We further showed that two host factors, the E2 ubiquitin-conjugating enzyme, UBE2E1, and the E3 ubiquitin ligase, CUL7, were important for supporting Dot/Icm translocation and L. pneumophila intracellular replication. In summary, we identified host ubiquitin pathways as important for the efficiency of Dot/Icm effector translocation by L. pneumophila, suggesting that host-derived ubiquitin-conjugating enzymes and ubiquitin ligases participate in the translocation of Legionella effector proteins and influence intracellular persistence and survival.
Comparative genomics revealed adaptive admixture in cryptosporidium hominis in Africa
Publisher: Microbiology Society
Date: 2021
Abstract: Cryptosporidiosis is a major cause of diarrhoeal illness among African children, and is associated with childhood mortality, malnutrition, cognitive development and growth retardation. Cryptosporidium hominis is the dominant pathogen in Africa, and genotyping at the glycoprotein 60 ( gp60 ) gene has revealed a complex distribution of different subtypes across this continent. However, a comprehensive exploration of the metapopulation structure and evolution based on whole-genome data has yet to be performed. Here, we sequenced and analysed the genomes of 26 C . hominis isolates, representing different gp60 subtypes, collected at rural sites in Gabon, Ghana, Madagascar and Tanzania. Phylogenetic and cluster analyses based on single-nucleotide polymorphisms showed that isolates predominantly clustered by their country of origin, irrespective of their gp60 subtype. We found a significant isolation-by-distance signature that shows the importance of local transmission, but we also detected evidence of hybridization between isolates of different geographical regions. We identified 37 outlier genes with exceptionally high nucleotide ersity, and this group is significantly enriched for genes encoding extracellular proteins and signal peptides. Furthermore, these genes are found more often than expected in recombinant regions, and they show a distinct signature of positive or balancing selection. We conclude that: (1) the metapopulation structure of C. hominis can only be accurately captured by whole-genome analyses (2) local anthroponotic transmission underpins the spread of this pathogen in Africa (3) hybridization occurs between distinct geographical lineages and (4) genetic introgression provides novel substrate for positive or balancing selection in genes involved in host–parasite coevolution.
Founder effect of the TTTCA repeat insertions in SAMD12 causing BAFME1
Publisher: Springer Science and Business Media LLC
Date: 09-11-2018
Tracing autism traits in large multiplex families to identify endophenotypes of the broader autism phenotype
Publisher: MDPI AG
Date: 27-10-2020
DOI: 10.3390/IJMS21217965
Abstract: Families comprising many in iduals with Autism Spectrum Disorders (ASD) may carry a dominant predisposing mutation. We implemented rigorous phenotyping of the “Broader Autism Phenotype” (BAP) in large multiplex ASD families using a novel endophenotype approach for the identification and characterisation of distinct BAP endophenotypes. We evaluated ASD/BAP features using standardised tests and a semi-structured interview to assess social, intellectual, executive and adaptive functioning in 110 in iduals, including two large multiplex families (Family A: 30 Family B: 35) and an independent s le of small families (n = 45). Our protocol identified four distinct psychological endophenotypes of the BAP that were evident across these independent s les, and showed high sensitivity (97%) and specificity (82%) for in iduals classified with the BAP. Patterns of inheritance of identified endophenotypes varied between the two large multiplex families, supporting their utility for identifying genes in ASD.
Identification of improved IL28B SNPs and haplotypes for prediction of drug response in treatment of hepatitis C using massively parallel sequencing in a cross-sectional European cohort
Publisher: Springer Science and Business Media LLC
Date: 2011
DOI: 10.1186/GM273
Unlocking the global antigenic diversity and balancing selection of Plasmodium falciparum
Publisher: Cold Spring Harbor Laboratory
Date: 26-06-2021
DOI: 10.1101/2021.06.21.21259065
Abstract: Investigation of the ersity of malaria parasite antigens can help prioritize and validate them as vaccine candidates and identify the most common variants for inclusion in vaccine formulations. Studies on Plasmodium falciparum antigen ersity have focused on well-known vaccine candidates while the ersity of several others has never been studied. Here we provide an overview of the ersity and population structure of leading vaccine candidate antigens of P. falciparum using the MalariaGEN Pf3K (version 5.1) resource, comprising more than 2600 genomes from 15 malaria endemic countries. We developed a stringent variant calling pipeline to extract high quality antigen gene sequences from the global dataset and a new R-package named VaxPack to streamline population genetic analyses. In addition, a newly developed algorithm that enables spatial averaging of selection pressure on 3D protein structures was applied to the dataset. We analysed the genes encoding 23 leading and novel candidate malaria vaccine antigens including csp , trap , eba175 , ama1 , rh5 , and CelTOS . We found that current malaria vaccine formulations are based on rare variants and thus may have limited efficacy. High levels of ersity with evidence of balancing selection was detected for most of the erythrocytic and pre-erythrocytic antigens. Measures of natural selection were then mapped to 3D protein structures to predict targets of functional antibodies. For some antigens, geographical variation in the intensity and distribution of these signals on the 3D structure suggests adaptations to different human host or mosquito vector populations. This study provides an essential framework for the ersity of P. falciparum antigens for inclusion in the design of the next generation of malaria vaccines. Highly effective malaria vaccines are important for the sustainable elimination of malaria. However, the ersity of parasite antigens targeted by malaria vaccines has been largely overlooked, with most vaccine formulations based only on a single antigen variant. Failure to accommodate this ersity may result in vaccines only being effective against vaccine-like variants, resulting in limited protective efficacy. Investigation of the ersity of genes encoding parasite antigens can help prioritize and validate them as vaccine candidates as well as to identify the most common variants for inclusion in the next generation of malaria vaccines. Here we measure the ersity of 23 vaccine antigens of Plasmodium falciparum , using the publicly available MalariaGEN Pf3K (version 5.1) resource comprising more than 2600 genomes from 15 malaria endemic countries. We found that variants found in current vaccine formulations are rare and thus may target only a small proportion of circulating malaria parasite strains. Variation in intensity of immune selection in parasites from different geographic areas suggests adaptation to different human host or vector populations. This study provides an essential framework for the design of the next generation of malaria vaccines, in addition to providing novel insights into malaria biology.
Comparing the frequency of common genetic variants and haplotypes between carriers and non-carriers of BRCA1 and BRCA2 deleterious mutations in Australian women diagnosed with breast cancer before 40 years of age
Publisher: Springer Science and Business Media LLC
Date: 09-2010
Harnessing gene expression networks to prioritize candidate Epileptic Encephalopathy genes
Publisher: Public Library of Science (PLoS)
Date: 09-07-2014
In silico prioritization based on coexpression can aid epileptic encephalopathy gene discovery
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 14-01-2016
High-resolution characterization of sequence signatures due to non-random cleavage of cell-free DNA
Publisher: Springer Science and Business Media LLC
Date: 17-06-2015
Defective lipid signalling caused by mutations in PIK3C2B underlies focal epilepsy
Publisher: Oxford University Press (OUP)
Date: 07-2022
Abstract: Epilepsy is one of the most frequent neurological diseases, with focal epilepsy accounting for the largest number of cases. The genetic alterations involved in focal epilepsy are far from being fully elucidated. Here, we show that defective lipid signalling caused by heterozygous ultra-rare variants in PIK3C2B, encoding for the class II phosphatidylinositol 3-kinase PI3K-C2β, underlie focal epilepsy in humans. We demonstrate that patients’ variants act as loss-of-function alleles, leading to impaired synthesis of the rare signalling lipid phosphatidylinositol 3,4-bisphosphate, resulting in mTORC1 hyperactivation. In vivo, mutant Pik3c2b alleles caused dose-dependent neuronal hyperexcitability and increased seizure susceptibility, indicating haploinsufficiency as a key driver of disease. Moreover, acute mTORC1 inhibition in mutant mice prevented experimentally induced seizures, providing a potential therapeutic option for a selective group of patients with focal epilepsy. Our findings reveal an unexpected role for class II PI3K-mediated lipid signalling in regulating mTORC1-dependent neuronal excitability in mice and humans.
An atlas of genetic influences on human blood metabolites
Publisher: Springer Science and Business Media LLC
Date: 11-05-2014
DOI: 10.1038/NG.2982
Genetic investigation into an increased susceptibility to biliary atresia in an extended New Zealand Māori family
Publisher: Springer Science and Business Media LLC
Date: 12-2018
Mosaic uniparental disomy results in GM1 gangliosidosis with normal enzyme assay
Publisher: Wiley
Date: 21-11-2018
DOI: 10.1002/AJMG.A.38549
Abstract: Inherited metabolic disorders are traditionally diagnosed using broad and expensive panels of screening tests, often including invasive skin and muscle biopsy. Proponents of next-generation genetic sequencing have argued that replacing these screening panels with whole exome sequencing (WES) would save money. Here, we present a complex patient in whom WES allowed diagnosis of GM1 gangliosidosis, caused by homozygous GLB1 mutations, resulting in β-galactosidase deficiency. A 10-year-old girl had progressive neurologic deterioration, macular cherry-red spot, and cornea verticillata. She had marked clinical improvement with initiation of the ketogenic diet. Comparative genomic hybridization microarray showed mosaic chromosome 3 paternal uniparental disomy (UPD). GM1 gangliosidosis was suspected, however β-galactosidase assay was normal. Trio WES identified a paternally-inherited pathogenic splice-site GLB1 mutation (c.75+2dupT). The girl had GM1 gangliosidosis however, enzymatic testing in blood was normal, presumably compensated for by non-UPD cells. Severe neurologic dysfunction occurred due to disruptive effects of UPD brain cells.
HFE p.C282Y homozygosity predisposes to rapid serum ferritin rise after menopause: A genotype‐stratified cohort study of hemochromatosis in Australian women
Publisher: Wiley
Date: 24-03-2017
DOI: 10.1111/JGH.13621
Increasingly inbred and fragmented populations of Plasmodium vivax associated with the eastward decline in malaria transmission across the Southwest Pacific
Publisher: Public Library of Science (PLoS)
Date: 26-01-2018
Genetic Disruption of Serine Biosynthesis is a Key Driver of Macular Telangiectasia Type 2 Etiology and Progression
Publisher: Cold Spring Harbor Laboratory
Date: 05-02-2020
DOI: 10.1101/2020.02.04.934356
Abstract: Macular telangiectasia type 2 (MacTel) is a rare, heritable and largely untreatable retinal disorder, often comorbid with diabetes. Genetic risk loci subtend retinal vascular calibre, and glycine/serine/threonine metabolism genes. Serine deficiency may contribute to MacTel via neurotoxic deoxysphingolipid production, however, an independent vascular contribution is also suspected. Here we use statistical genetics to dissect the causal mechanisms underpinning this complex disease. We integrated genetic markers for MacTel, vascular, and metabolic traits, and applied Mendelian randomization, MTAG, and conditional/interaction genome-wide association analysis to discover causal contributors to both disease, and spatial retinal imaging sub-phenotypes. Serine was a key causal driver of disease occurrence and progression, with a lesser contribution to type 2 diabetes risk. Conversely, glycine, threonine and retinal vascular traits are unlikely to be causal for MacTel. Conditional regression analysis resolved three novel disease loci independent of endogenous serine biosynthetic capacity. By aggregating retinal phenotypes into endophenotypes, we demonstrate that SNPs constituting independent risk loci act via related endophenotypes. Our findings will aid in early diagnosis and accurate prognosis of MacTel, and improve prospects for effective therapeutic intervention. Our integrative genetics approach also serves as a useful template for post-GWAS analyses in other disorders.
Cpipe: A shared variant detection pipeline designed for diagnostic settings
Publisher: Springer Science and Business Media LLC
Date: 10-07-2015
A novel X-linked form of congenital fiber-type disproportion
Publisher: Wiley
Date: 2005
DOI: 10.1002/ANA.20644
Abstract: We describe a four-generation family with a previously unreported form of congenital fiber-type disproportion that follows an X-linked inheritance pattern. Affected male family members have a striking pattern of weakness. From birth there is marked ptosis, facial weakness, poor sucking, hypotonia, respiratory weakness, and relatively preserved limb strength. Most affected male in iduals die of respiratory failure within the first months of life. A mild dilated cardiomyopathy developed in infancy in the sole surviving affected male member of this family. Some carrier female in iduals manifest milder signs. We have demonstrated linkage to two regions of the X chromosome, Xp22.13 to Xp11.4 and Xq13.1 to Xq22.1, with a maximum logarithm of odds score of 3.25 in the latter region. We propose that clinical clues can differentiate this disorder from other forms of congenital fiber-type disproportion so that affected families can receive appropriate genetic counseling.
Estimation of age-standardized net survival, even when age-specific data are sparse
Publisher: Elsevier BV
Date: 08-2020
Probabilistic analysis of recessive mutagenesis screen strategies
Publisher: Springer Science and Business Media LLC
Date: 2007
DOI: 10.1007/S00335-006-0057-Z
Abstract: Random mutagenesis screens for recessive phenotypes require three generations of breeding, using either a backcross (BC) or intercross (IC) strategy. Hence, they are more costly and technically demanding than those for dominant phenotypes. Maximizing the return from these screens requires maximizing the number of mutations that are bred to homozyosity in the G(3) generation. Using a probabilistic approach, we compare different designs of screens for recessive phenotypes and the impact each one has on the number of mutations that can be effectively screened. We address the issue of BC versus IC strategies and consider genome-wide, region-specific screens and suppressor screens. We find that optimally designed BC and IC screens allow the screening of, on average, similar numbers of mutations but that interpedigree variation is more pronounced when the IC strategy is employed. By conducting a retrospective analysis of published mutagenesis screens, we show that, depending on the strategy, a threefold difference in the numbers of mutations screened per animal used could be expected. This method allows researchers to contrast, for a range of experimental designs, the cost per mutation screened and to maximize the number of mutations that one can expect to screen in a given experiment.
Generation of seven iPSC lines from peripheral blood mononuclear cells suitable to investigate Autism Spectrum Disorder.
Publisher: Elsevier BV
Date: 08-2019
DOI: 10.1016/J.SCR.2019.101516
Abstract: We have generated and characterized seven human induced pluripotent stem cell (iPSC) lines derived from peripheral blood mononuclear cells (PBMCs) from a single family, including unaffected and affected in iduals clinically diagnosed with Autism Spectrum Disorder (ASD). The reprogramming of the PBMCs was performed using non-integrative Sendai virus containing the reprogramming factors POU5F1 (OCT4), SOX2, KLF4 and MYC. All iPSC lines exhibited a normal karyotype and pluripotency was validated by immunofluorescence, flow cytometry and their ability to differentiate into the three embryonic germ layers. These iPSC lines are a valuable resource to study the molecular mechanisms underlying ASD.
Human and mouse mutations in WDR35 cause short-rib polydactyly syndromes due to abnormal ciliogenesis
Publisher: Elsevier BV
Date: 04-2011
A novel intronic GAA repeat expansion inFGF14causes autosomal dominant adult-onset ataxia (SCA50, ATX-FGF14)
Publisher: Cold Spring Harbor Laboratory
Date: 25-03-0025
DOI: 10.1101/2022.10.21.22281020
Abstract: Adult-onset cerebellar ataxias are a group of neurodegenerative conditions that challenge both genetic discovery and molecular diagnosis. In this study, we identified a novel intronic GAA repeat expansion in the gene encoding Fibroblast Growth Factor 14 ( FGF14 ). Genetic analysis identified 4/95 previously unresolved Australian affected in iduals (4.2%) with (GAA) and a further nine in iduals with (GAA) . Notably, PCR and long-read sequence analysis revealed these were pure GAA repeats. In comparison, no controls had (GAA) and only 2/311 control in iduals (0.6%) encoded a pure (GAA) . In a German validation cohort 9/104 (8.7%) of affected in iduals had (GAA) and a further six had (GAA) . In comparison no controls had (GAA) and 10/190 (5.3%) encoded (GAA) . The combined data suggests (GAA) are disease-causing and fully penetrant [P-value 6.0×10 −8 , OR 72 (95% CI=4.3-1227)], while (GAA) is likely pathogenic, albeit with reduced penetrance. Affected in iduals had an adult-onset, slowly progressive cerebellar ataxia with a clinical phenotype that may include vestibular impairment, hyper-reflexia and autonomic dysfunction. A negative correlation between age at onset and repeat length was observed (R2=0.44 p=0.00045, slope = -0.12). This study demonstrates the power of genome sequencing and advanced bioinformatic tools to identify novel repeat expansion loci via model free, genome-wide analysis and identifies SCA50/ATX-FGF14 is a frequent cause of adult-onset ataxia.
Validation of new bioinformatic tools to identify expanded repeats: A non-reference intronic pentamer expansion in RFC1 causes CANVAS
Publisher: Cold Spring Harbor Laboratory
Date: 04-04-2019
DOI: 10.1101/597781
Abstract: Genomic technologies such as Next Generation Sequencing (NGS) are revolutionizing molecular diagnostics and clinical medicine. However, these approaches have proven inefficient at identifying pathogenic repeat expansions. Here, we apply a collection of bioinformatics tools that can be utilized to identify either known or novel expanded repeat sequences in NGS data. We performed genetic studies of a cohort of 35 in iduals from 22 families with a clinical diagnosis of cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS). Analysis of whole genome sequence (WGS) data with five independent algorithms identified a recessively inherited intronic repeat expansion [(AAGGG) exp ] in the gene encoding Replication Factor C1 ( RFC1 ). This motif, not reported in the reference sequence, localized to an Alu element and replaced the reference (AAAAG) 11 short tandem repeat. Genetic analyses confirmed the pathogenic expansion in 18 of 22 CANVAS families and identified a core ancestral haplotype, estimated to have arisen in Europe over twenty-five thousand years ago. WGS of the four RFC1 negative CANVAS families identified plausible variants in three, with genomic re-diagnosis of SCA3, spastic ataxia of the Charlevoix-Saguenay type and SCA45. This study identified the genetic basis of CANVAS and demonstrated that these improved bioinformatics tools increase the diagnostic utility of WGS to determine the genetic basis of a heterogeneous group of clinically overlapping neurogenetic disorders.
EIF2S3 Mutations Associated with Severe X-Linked Intellectual Disability Syndrome MEHMO
Publisher: Hindawi Limited
Date: 23-01-2017
DOI: 10.1002/HUMU.23170
Closing the case of APOE in multiple sclerosis: No association with disease risk in over 29 000 subjects
Publisher: BMJ
Date: 09-2012
DOI: 10.1136/JMEDGENET-2012-101175
Abstract: Single nucleotide polymorphisms (SNPs) rs429358 (ε4) and rs7412 (ε2), both invoking changes in the amino-acid sequence of the apolipoprotein E (APOE) gene, have previously been tested for association with multiple sclerosis (MS) risk. However, none of these studies was sufficiently powered to detect modest effect sizes at acceptable type-I error rates. As both SNPs are only imperfectly captured on commonly used microarray genotyping platforms, their evaluation in the context of genome-wide association studies has been hindered until recently. We genotyped 12 740 subjects hitherto not studied for their APOE status, imputed raw genotype data from 8739 subjects from five independent genome-wide association studies datasets using the most recent high-resolution reference panels, and extracted genotype data for 8265 subjects from previous candidate gene assessments. Despite sufficient power to detect associations at genome-wide significance thresholds across a range of ORs, our analyses did not support a role of rs429358 or rs7412 on MS susceptibility. This included meta-analyses of the combined data across 13 913 MS cases and 15 831 controls (OR=0.95, p=0.259, and OR 1.07, p=0.0569, for rs429358 and rs7412, respectively). Given the large s le size of our analyses, it is unlikely that the two APOE missense SNPs studied here exert any relevant effects on MS susceptibility.
Evidence of linkage to chromosome 5p13.2-q11.1 in a large inbred family with genetic generalized epilepsy
Publisher: Wiley
Date: 04-07-2018
DOI: 10.1111/EPI.14506
Abstract: The clinical genetics of genetic generalized epilepsy suggests complex inheritance large pedigrees, with multiple affected in iduals, are rare exceptions. We studied a large consanguineous family from Turkey where extensive electroclinical phenotyping revealed a familial phenotype most closely resembling juvenile myoclonic epilepsy. For a subject to be considered affected (n = 14), a diagnostic electroencephalogram was required. Seizure onset ranged between 6 and 19 years (mean = 12 years). Thirteen of 14 experienced myoclonic jerks in 11, this was associated with eyelid blinking, and in 10 it was interspersed with absences. Generalized tonic-clonic seizures were seen in 11. One in idual had generalized tonic-clonic seizures alone. Electroencephalograms demonstrated generalized polyspike and wave discharges that were not associated with photoparoxysmal response. Intellect was normal. Nineteen family members were subsequently chosen for nonparametric multipoint linkage analyses, which identified a 39.5 Mb region on chromosome 5 (P < 0.0001). Iterative analysis, including discovery of a subtly affected in idual, narrowed the critical region to 15.4 Mb and possibly to 5.5 Mb. Homozygous versus heterozygous state of the refined 5p13.2-q11.1 haplotype was not associated with phenotypic severity or onset age, suggesting that one versus two pathogenic variants may result in similar phenotypes. Whole exome sequencing (n = 3) failed to detect any rare, protein-coding variants within the highly significant linkage region that includes HCN1 as a promising candidate.
Early neuroimaging markers of FOXP2 intragenic deletion
Publisher: Springer Science and Business Media LLC
Date: 13-10-2016
DOI: 10.1038/SREP35192
Abstract: FOXP2 is the major gene associated with severe, persistent, developmental speech and language disorders. While studies in the original family in which a FOXP2 mutation was found showed volume reduction and reduced activation in core language and speech networks, there have been no imaging studies of different FOXP2 mutations. We conducted a multimodal MRI study in an eight-year-old boy (A-II) with a de novo FOXP2 intragenic deletion. A-II showed marked bilateral volume reductions in the hippoc us, thalamus, globus pallidus, and caudate nucleus compared with 26 control males (effect sizes from −1 to −3). He showed no detectable functional MRI activity when repeating nonsense words. The hippoc us is implicated for the first time in FOXP2 diseases. We conclude that FOXP2 anomaly is either directly or indirectly associated with atypical development of widespread subcortical networks early in life.
Loss-of-function mutations of ILDR1 cause autosomal-recessive hearing impairment DFNB42
Publisher: Elsevier BV
Date: 02-2011
Germline variants in tumor suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome
Publisher: Elsevier BV
Date: 04-2022
Identification of genetic factors influencing metabolic dysregulation and retinal support for MacTel, a retinal disorder
Publisher: Springer Science and Business Media LLC
Date: 02-03-2021
DOI: 10.1038/S42003-021-01788-W
Abstract: Macular Telangiectasia Type 2 (MacTel) is a rare degenerative retinal disease with complex genetic architecture. We performed a genome-wide association study on 1,067 MacTel patients and 3,799 controls, which identified eight novel genome-wide significant loci ( p 5 × 10 −8 ), and confirmed all three previously reported loci. Using MAGMA, eQTL and transcriptome-wide association analysis, we prioritised 48 genes implicated in serine-glycine biosynthesis, metabolite transport, and retinal vasculature and thickness. Mendelian randomization indicated a likely causative role of serine (FDR = 3.9 × 10 − 47 ) and glycine depletion (FDR = 0.006) as well as alanine abundance (FDR = 0.009). Polygenic risk scoring achieved an accuracy of 0.74 and was associated in UKBiobank with retinal damage ( p = 0.009). This represents the largest genetic study on MacTel to date and further highlights genetically-induced systemic and tissue-specific metabolic dysregulation in MacTel patients, which impinges on retinal health.
iPSC-derived retinal pigmented epithelial cells from patients with macular telangiectasia show decreased mitochondrial function
Publisher: American Society for Clinical Investigation
Date: 05-2023
DOI: 10.1172/JCI163771
Iron-Overload–Related Disease inHFEHereditary Hemochromatosis
Publisher: Massachusetts Medical Society
Date: 17-01-2008
DOI: 10.1056/NEJMOA073286
Identification of genetic factors influencing metabolic dysregulation and retinal support for MacTel, a retinal disorder
Publisher: Cold Spring Harbor Laboratory
Date: 04-08-2020
DOI: 10.1101/2020.08.02.20161117
Abstract: Macular Telangiectasia Type 2 (MacTel) is a rare degenerative retinal disease with complex genetic architecture. We performed a genome-wide association study on 1,067 MacTel patients and 3,799 controls, which identified eight novel genome-wide significant loci (p E-8), and confirmed all three previously reported loci. Using MAGMA, eQTL and transcriptome-wide association analysis, we prioritised 48 genes implicated in serine-glycine biosynthesis, metabolite transport, and retinal vasculature and thickness. Mendelian randomization indicated a likely causative role of serine (FDR=3.9E-47) and glycine depletion (FDR=0.006) as well as alanine abundance (FDR=0.009). Polygenic risk scoring achieved an accuracy of 0.74 and was associated in UKBiobank with retinal damage (p=0.009). This represents the largest genetic study on MacTel to date, and further highlights genetically-induced systemic and tissue-specific metabolic dysregulation in MacTel patients, which impinges on retinal health.
Functional analysis of a hypomorphic allele shows that MMP14 catalytic activity is the prime determinant of the Winchester syndrome phenotype
Publisher: Oxford University Press (OUP)
Date: 08-05-2018
DOI: 10.1093/HMG/DDY168
Identity by descent fine mapping of familial adult myoclonus epilepsy (FAME) to 2p11.2–2q11.2
Publisher: Springer Science and Business Media LLC
Date: 07-2016
DOI: 10.1007/S00439-016-1700-8
Abstract: Familial adult myoclonus epilepsy (FAME) is a rare autosomal dominant disorder characterized by adult onset, involuntary muscle jerks, cortical myoclonus and occasional seizures. FAME is genetically heterogeneous with more than 70 families reported worldwide and five potential disease loci. The efforts to identify potential causal variants have been unsuccessful in all but three families. To date, linkage analysis has been the main approach to find and narrow FAME critical regions. We propose an alternative method, pedigree free identity-by-descent (IBD) mapping, that infers regions of the genome between in iduals that have been inherited from a common ancestor. IBD mapping provides an alternative to linkage analysis in the presence of allelic and locus heterogeneity by detecting clusters of in iduals who share a common allele. Succeeding IBD mapping, gene prioritization based on gene co-expression analysis can be used to identify the most promising candidate genes. We performed an IBD analysis using high-density single nucleotide polymorphism (SNP) array data followed by gene prioritization on a FAME cohort of ten European families and one Australian/New Zealander family eight of which had known disease loci. By identifying IBD regions common to multiple families, we were able to narrow the FAME2 locus to a 9.78 megabase interval within 2p11.2-q11.2. We provide additional evidence of a founder effect in four Italian families and allelic heterogeneity with at least four distinct founders responsible for FAME at the FAME2 locus. In addition, we suggest candidate disease genes using gene prioritization based on gene co-expression analysis.
Genome-wide linkage scan and association study of PARL to the expression of LHON families in Thailand
Publisher: Springer Science and Business Media LLC
Date: 21-04-2010
DOI: 10.1007/S00439-010-0821-8
Abstract: Leber hereditary optic neuropathy (LHON) is the most common mitochondrially inherited disease causing blindness, preferentially in young adult males. Most of the patients carry the G11778A mitochondrial DNA (mtDNA) mutation. However, the marked incomplete penetrance and the gender bias indicate some additional genetic and/or environmental factors to disease expression. Herein, we first conducted a genome-wide linkage scan with 400 microsatellite markers in 9 large Thai LHON G11778A pedigrees. Using an affecteds-only nonparametric linkage analysis, 4 regions on chromosomes 3, 12, 13 and 18 showed Zlr scores greater than 2 (P 2 in 10 of 16 allele sharing models tested) was then expanded to include the region 3q26.2-3q28 covering SLC7A14 (3q26.2), MFN1 (3q26.32), MRPL47 (3q26.33), MCCC1 (3q27.1), PARL (3q27.1) and OPA1 (3q28-q29). All of these candidate genes were selected from the Maestro database and had known to be localized in mitochondria. Sixty tag SNPs were genotyped in 86 cases, 211 of their relatives and 32 unrelated Thai controls, by multiplex-PCR-based Invader assay. Analyses using a powerful association testing tool that adjusts for relatedness (the M(QLS) statistic) showed the most evidence of association between two SNPs, rs3749446 and rs1402000 (located in PARL presenilins-associated rhomboid-like) and LHON expression (both P = 8.8 x 10(-5)). The mitochondrial PARL protease has been recently known to play a role with a dynamin-related OPA1 protein in preventing apoptotic events by slowing down the release of cytochrome c out of mitochondrial cristae junctions. Moreover, PARL is required to activate the intramembranous proteolyses resulting in the degradation of an accumulated pro-apoptotic protein in the outer mitochondrial membrane. Under these circumstances, variants of PARL are suggested to influence cell death by apoptosis which has long been believed to intrigue the neurodegeneration of LHON.
Keipert syndrome (Nasodigitoacoustic syndrome) is X-linked and maps to Xq22.2–Xq28
Publisher: Wiley
Date: 2007
DOI: 10.1002/AJMG.A.31917
Abstract: Keipert syndrome is a rare condition comprising sensorineural deafness associated with facial and digital abnormalities. To date, Keipert syndrome has been reported in six male patients including two sib pairs however the genetic basis of Keipert syndrome is yet to be elucidated. We report on the diagnosis of Keipert syndrome in the nephew of the brothers in the first report of Keipert syndrome, with a pedigree consistent with X-linked recessive inheritance. Linkage analysis using microsatellite markers along the X-chromosome suggests that the gene for Keipert syndrome is located in the region Xq22.2-Xq28. We postulate the Keipert syndrome is caused by a novel gene at Xq22.2-Xq28.
Progressive Myoclonus Epilepsy Caused by a Homozygous Splicing Variant of SLC7A6OS
Publisher: Wiley
Date: 05-11-2021
DOI: 10.1002/ANA.25941
Abstract: Exome sequencing was performed in 2 unrelated families with progressive myoclonus epilepsy. Affected in iduals from both families shared a rare, homozygous c.191A G variant affecting a splice site in SLC7A6OS . Analysis of cDNA from lymphoblastoid cells demonstrated partial splice site abolition and the creation of an abnormal isoform. Quantitative reverse transcriptase polymerase chain reaction and Western blot showed a marked reduction of protein expression. Haplotype analysis identified a ~0.85cM shared genomic region on chromosome 16q encompassing the c.191A G variant, consistent with a distant ancestor common to both families. Our results suggest that biallelic loss‐of‐function variants in SLC7A6OS are a novel genetic cause of progressive myoclonus epilepsy. ANN NEUROL 2021 :402–407
Cross-platform genetic discovery of small molecule products of metabolism and application to clinical outcomes
Publisher: Cold Spring Harbor Laboratory
Date: 04-02-2020
DOI: 10.1101/2020.02.03.932541
Abstract: Circulating levels of small molecules or metabolites are highly heritable, but the impact of genetic differences in metabolism on human health is not well understood. In this cross-platform, genome-wide meta-analysis of 174 metabolite levels across six cohorts including up to 86,507 participants (70% unpublished data), we identify 499 (362 novel) genome-wide significant associations (p .9×10 -10 ) at 144 (94 novel) genomic regions. We show that inheritance of blood metabolite levels in the general population is characterized by pleiotropy, allelic heterogeneity, rare and common variants with large effects, non-linear associations, and enrichment for nonsynonymous variation in transporter and enzyme encoding genes. The majority of identified genes are known to be involved in biochemical processes regulating metabolite levels and to cause monogenic inborn errors of metabolism linked to specific metabolites, such as ASNS (rs17345286, MAF=0.27) and asparagine levels. We illustrate the influence of metabolite-associated variants on human health including a shared signal at GLP2R (p.Asp470Asn) associated with higher citrulline levels, body mass index, fasting glucose-dependent insulinotropic peptide and type 2 diabetes risk, and demonstrate beta-arrestin signalling as the underlying mechanism in cellular models. We link genetically-higher serine levels to a 95% reduction in the likelihood of developing macular telangiectasia type 2 [odds ratio (95% confidence interval) per standard deviation higher levels 0.05 (0.03-0.08 p=9.5×10 -30 )]. We further demonstrate the predictive value of genetic variants identified for serine or glycine levels for this rare and difficult to diagnose degenerative retinal disease [area under the receiver operating characteristic curve: 0.73 (95% confidence interval: 0.70-0.75)], for which low serine availability, through generation of deoxysphingolipids, has recently been shown to be causally relevant. These results show that integration of human genomic variation with circulating small molecule data obtained across different measurement platforms enables efficient discovery of genetic regulators of human metabolism and translation into clinical insights.
Genes4Epilepsy: An epilepsy gene resource
Publisher: Wiley
Date: 09-03-2023
DOI: 10.1111/EPI.17547
Abstract: “How many epilepsy genes are there?” is a frequently asked question. We sought to (1) provide a curated list of genes that cause monogenic epilepsies, and (2) compare and contrast epilepsy gene panels from multiple sources. We compared genes included on the epilepsy panels (as of July 29, 2022) of four clinical diagnostic providers: Invitae, GeneDx, Fulgent Genetics, and Blueprint Genetics and two research resources: PanelApp Australia and ClinGen. A master list of all unique genes was supplemented by additional genes identified via PubMed searches up until August 15, 2022, using the search terms “genetics” AND/OR “epilepsy” AND/OR “seizures”. Evidence supporting a monogenic role for all genes was manually reviewed those with limited or disputed evidence were excluded. All genes were annotated according to inheritance pattern and broad epilepsy phenotype. The comparison of genes included on epilepsy clinical panels revealed high heterogeneity in both number of genes (range: 144–511) and content. Just 111 genes (15.5%) were included on all four clinical panels. Subsequent manual curation of all “epilepsy genes” identified monogenic etiologies. Almost 90% of genes were associated with developmental and epileptic encephalopathies. By comparison only 5% of genes were associated with monogenic causes of “common epilepsies” (i.e., generalized and focal epilepsy syndromes). Autosomal recessive genes were most frequent (56% of genes) however, this varied according to the associated epilepsy phenotype(s). Genes associated with common epilepsy syndromes were more likely to be dominantly inherited and associated with multiple epilepsy types. Our curated list of monogenic epilepsy genes is publicly available: ahlolab/genes4epilepsy and will be regularly updated. This gene resource can be utilized to target genes beyond those included on clinical gene panels, for gene enrichment methods and candidate gene prioritization. We invite ongoing feedback and contributions from the scientific community via genes4-epilepsy@unimelb.edu.au .
Mutations in RAB39B cause X-linked intellectual disability and early-onset parkinson disease with α-synuclein pathology
Publisher: Elsevier BV
Date: 12-2014
Evidence for a common genetic aetiology in high-risk families with multiple haematological malignancy subtypes
Publisher: Wiley
Date: 08-2010
DOI: 10.1111/J.1365-2141.2010.08267.X
Abstract: A family history of a haematological malignancy (HM) is known to be a risk factor for HMs. However, collections of large families with multiple cases of varied disease types are relatively rare. We describe a collection of 12 families with dense aggregations of multiple HM subtypes. Cases were ascertained from a population based study conducted between 1972 and 1980 in Tasmania, Australia. Diagnoses were confirmed through review and re-examination of stored tissue, pathology reports, Tasmanian Cancer Registry and flow cytometry records. Family trees were generated and kinship coefficients were calculated for all pairs of affected in iduals. 120 cases were found in these families. Cases diagnosed with chronic lymphocytic leukaemia (CLL) demonstrated the most significantly increased aggregation (P 53 years), did not aggregate together in families with disease that presented at an earlier age (<20 years) (P = 0.009).
Severe childhood speech disorder: Gene discovery highlights transcriptional dysregulation
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 28-04-2020
DOI: 10.1212/WNL.0000000000009441
Abstract: Determining the genetic basis of speech disorders provides insight into the neurobiology of human communication. Despite intensive investigation over the past 2 decades, the etiology of most speech disorders in children remains unexplained. To test the hypothesis that speech disorders have a genetic etiology, we performed genetic analysis of children with severe speech disorder, specifically childhood apraxia of speech (CAS). Precise phenotyping together with research genome or exome analysis were performed on children referred with a primary diagnosis of CAS. Gene coexpression and gene set enrichment analyses were conducted on high-confidence gene candidates. Thirty-four probands ascertained for CAS were studied. In 11/34 (32%) probands, we identified highly plausible pathogenic single nucleotide (n = 10 CDK13 , EBF3 , GNAO1 , GNB1 , DDX3X , MEIS2 , POGZ , SETBP1 , UPF2 , ZNF142 ) or copy number (n = 1 5q14.3q21.1 locus) variants in novel genes or loci for CAS. Testing of parental DNA was available for 9 probands and confirmed that the variants had arisen de novo. Eight genes encode proteins critical for regulation of gene transcription, and analyses of transcriptomic data found CAS-implicated genes were highly coexpressed in the developing human brain. We identify the likely genetic etiology in 11 patients with CAS and implicate 9 genes for the first time. We find that CAS is often a sporadic monogenic disorder, and highly genetically heterogeneous. Highly penetrant variants implicate shared pathways in broad transcriptional regulation, highlighting the key role of transcriptional regulation in normal speech development. CAS is a distinctive, socially debilitating clinical disorder, and understanding its molecular basis is the first step towards identifying precision medicine approaches.
Cluster Headache: Comparing clustering tools for 10x single cell sequencing data
Publisher: Cold Spring Harbor Laboratory
Date: 16-10-2017
DOI: 10.1101/203752
Abstract: The commercially available 10X Genomics protocol to generate droplet-based single cell RNA-seq (scRNA-seq) data is enjoying growing popularity among researchers. Fundamental to the analysis of such scRNA-seq data is the ability to cluster similar or same cells into non-overlapping groups. Many competing methods have been proposed for this task, but there is currently little guidance with regards to which method offers most accuracy. Answering this question is complicated by the fact that 10X Genomics data lack cell labels that would allow a direct performance evaluation. Thus in this review, we focused on comparing clustering solutions of a dozen methods for three datasets on human peripheral mononuclear cells generated with the 10X Genomics technology. While clustering solutions appeared robust, we found that solutions produced by different methods have little in common with each other. They also failed to replicate cell type assignment generated with supervised labeling approaches. Furthermore, we demonstrate that all clustering methods tested clustered cells to a large degree according to the amount of genes coding for ribosomal protein genes in each cell.
Reducing the exome search space for Mendelian diseases using genetic linkage analysis of exome genotypes
Publisher: Springer Science and Business Media LLC
Date: 2011
Somatic Mosaic Pathogenic Variant Gradient Detected in Trace Brain Tissue from Stereo-EEG Depth Electrodes
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-12-2022
DOI: 10.1212/WNL.0000000000201469
Abstract: Mosaic pathogenic variants restricted to the brain are increasingly recognized as a cause of focal epilepsies. We aimed to identify a mosaic pathogenic variant and its anatomical gradient in brain DNA derived from trace tissue on explanted stereoelectroencephalography (SEEG) electrodes. We studied a patient with nonlesional multifocal epilepsy undergoing presurgical evaluation with SEEG. After explantation, the electrodes were ided into 3 pools based on their brain location (right posterior quadrant, left posterior quadrant, hippoc us/temporal neocortex). Tissue from each pool was processed for trace DNA that was whole genome lified prior to high-depth exome sequencing. Droplet digital PCR was performed to quantify mosaicism. A brain-specific glial fibrillary acidic protein (GFAP) assay enabled cell-of-origin analysis. We demonstrated a mosaic gradient for a novel pathogenic KCNT1 loss-of-function variant (c.530G A, p.W177X) predicted to lead to nonsense-mediated decay. Strikingly, the mosaic gradient correlated strongly with the SEEG findings because the highest variant allele frequency was in the right posterior quadrant, reflecting the most epileptogenic region on EEG studies. An elevated GFAP level indicated enrichment of brain-derived cells in SEEG cell suspension. This study demonstrates a proof of concept that mosaic gradients of pathogenic variants can be established using trace tissue from explanted SEEG electrodes.
SNP selection for genes of iron metabolism in a study of genetic modifiers of hemochromatosis
Publisher: Springer Science and Business Media LLC
Date: 20-03-2008
Erratum: Author Correction: Identification of genetic factors influencing metabolic dysregulation and retinal support for MacTel, a retinal disorder (Communications biology (2021) 4 1 (274))
Publisher: Springer Science and Business Media LLC
Date: 09-04-2021
DOI: 10.1038/S42003-021-01972-Y
Abstract: A Correction to this paper has been published: 0.1038/s42003-021-01972-y
Global diversity and balancing selection of 23 leading Plasmodium falciparum candidate vaccine antigens
Publisher: Public Library of Science (PLoS)
Date: 02-02-2022
DOI: 10.1371/JOURNAL.PCBI.1009801
Abstract: Investigation of the ersity of malaria parasite antigens can help prioritize and validate them as vaccine candidates and identify the most common variants for inclusion in vaccine formulations. Studies of vaccine candidates of the most virulent human malaria parasite, Plasmodium falciparum , have focused on a handful of well-known antigens, while several others have never been studied. Here we examine the global ersity and population structure of leading vaccine candidate antigens of P . falciparum using the MalariaGEN Pf3K (version 5.1) resource, comprising more than 2600 genomes from 15 malaria endemic countries. A stringent variant calling pipeline was used to extract high quality antigen gene ‘haplotypes’ from the global dataset and a new R-package named VaxPack was used to streamline population genetic analyses. In addition, a newly developed algorithm that enables spatial averaging of selection pressure on 3D protein structures was applied to the dataset. We analysed the genes encoding 23 leading and novel candidate malaria vaccine antigens including csp , trap , eba175 , ama1 , rh5 , and CelTOS . Our analysis shows that current malaria vaccine formulations are based on rare haplotypes and thus may have limited efficacy against natural parasite populations. High levels of ersity with evidence of balancing selection was detected for most of the erythrocytic and pre-erythrocytic antigens. Measures of natural selection were then mapped to 3D protein structures to predict targets of functional antibodies. For some antigens, geographical variation in the intensity and distribution of these signals on the 3D structure suggests adaptation to different human host or mosquito vector populations. This study provides an essential framework for the ersity of P . falciparum antigens to be considered in the design of the next generation of malaria vaccines.
Variable hearing impairment in a DFNB2 family with a novel MYO7A missense mutation
Publisher: Wiley
Date: 04-02-2010
Maturity-onset diabetes of the young type 5 in a family with diabetes and mild kidney disease diagnosed by whole exome sequencing
Publisher: Wiley
Date: 11-2014
DOI: 10.1111/IMJ.12584
Abstract: Exome sequencing is being increasingly used to identify disease-associated gene mutations. We used whole exome sequencing to determine the genetic basis of a syndrome of diabetes and renal disease affecting a mother and her son. We identified a mutation in the hepatocyte nuclear factor 1-b (HNF1B) gene that encoded a methionine to valine amino acid change (M160V) in the HNF1B protein. This leads us to the previously unappreciated diagnosis of maturity-onset diabetes of the young type 5 and provided a basis for genetic counselling of other family members.
Candidate disease gene prediction using Gentrepid: application to a genome-wide association study on coronary artery disease.
Publisher: Wiley
Date: 13-11-2014
DOI: 10.1002/MGG3.40
Progressive myoclonus epilepsies—Residual unsolved cases have marked genetic heterogeneity including dolichol-dependent protein glycosylation pathway genes
Publisher: Elsevier BV
Date: 04-2021
Genetic aetiologies for childhood speech disorder: novel pathways co-expressed during brain development
Publisher: Cold Spring Harbor Laboratory
Date: 16-05-2022
DOI: 10.1101/2022.05.15.22274630
Abstract: Childhood apraxia of speech (CAS), the prototypic severe childhood speech disorder, is characterized by motor programming and planning deficits. Genetic factors make substantive contributions to CAS aetiology, with a monogenic pathogenic variant identified in a third of cases, implicating around 20 single genes to date. Here we ascertained 70 unrelated probands with a clinical diagnosis of CAS and performed trio genome sequencing. Our bioinformatic analysis examined single nucleotide, indel, copy number, structural and short tandem repeat variants. We prioritised appropriate variants arising de novo or inherited that were expected to be damaging based on in silico predictions. We identified high confidence variants in 18/70 (26%) probands, almost doubling the current number of candidate genes for CAS. Three of the 18 variants affected SETBP1 , SETD1A and DDX3X , thus confirming their roles in CAS, while the remaining 15 occurred in genes not previously associated with this disorder. Fifteen variants arose de novo and three were inherited. We provide further novel insights into the biology of child speech disorder, highlighting the roles of chromatin organization and gene regulation in CAS, and confirm that genes involved in CAS are co-expressed during brain development. Our findings confirm a diagnostic yield comparable to, or even higher, than other neurodevelopmental disorders with substantial de novo variant burden. Data also support the increasingly recognised overlaps between genes conferring risk for a range of neurodevelopmental disorders. Understanding the aetiological basis of CAS is critical to end the diagnostic odyssey and ensure affected in iduals are poised for precision medicine trials.
Inherited RORB pathogenic variants: Overlap of photosensitive genetic generalized and occipital lobe epilepsy
Publisher: Wiley
Date: 12-03-2020
DOI: 10.1111/EPI.16475
GFI1B mutation causes a bleeding disorder with abnormal platelet function
Publisher: Elsevier BV
Date: 11-2013
DOI: 10.1111/JTH.12368
Abstract: GFI1B is a transcription factor important for erythropoiesis and megakaryocyte development but previously unknown to be associated with human disease. A family with a novel bleeding disorder was identified and characterized. Genetic linkage analysis and massively parallel sequencing were used to localize the mutation causing the disease phenotype on chromosome 9. Functional studies were then performed in megakaryocytic cell lines to determine the biological effects of the mutant transcript. We have identified a family with an autosomal dominant bleeding disorder associated with macrothrombocytopenia, red cell anisopoikilocytosis, and platelet dysfunction. The severity of bleeding is variable with some affected in iduals experiencing spontaneous bleeding while other family members exhibit only abnormal bleeding with surgery. A single nucleotide insertion was identified in GFI1B that predicts a frameshift mutation in the fifth zinc finger DNA-binding domain. This mutation alters the transcriptional activity of the protein, resulting in a reduction in platelet α-granule content and aberrant expression of key platelet proteins. GFI1B mutation represents a novel human bleeding disorder, and the described phenotype identifies GFI1B as a critical regulator of platelet shape, number, and function.
Cell-specific cis-regulatory elements and mechanisms of non-coding genetic disease in human retina and retinal organoids
Publisher: Elsevier BV
Date: 03-2022
New insights into malaria susceptibility from the genomes of 17,000 individuals from Africa, Asia, and Oceania
Publisher: Cold Spring Harbor Laboratory
Date: 04-02-2019
DOI: 10.1101/535898
Abstract: We conducted a genome-wide association study of host resistance to severe Plasmodium falciparum malaria in over 17,000 in iduals from 11 malaria-endemic countries, undertaking a wide ranging analysis which identifies five replicable associations with genome-wide levels of evidence. Our findings include a newly implicated variant on chromosome 6 associated with risk of cerebral malaria, and the discovery of an erythroid-specific transcription start site underlying the association in ATP2B4 . Previously reported HLA associations cannot be replicated in this dataset. We estimate substantial heritability of severe malaria ( h 2 ~ 23%), of which around 10% is explained by the currently identified associations. Our dataset will provide a major building block for future research on the genetic determinants of disease in these erse human populations.
Atypical development of Broca’s area in a large family with inherited stuttering
Publisher: Oxford University Press (OUP)
Date: 23-11-2021
Abstract: Developmental stuttering is a condition of speech dysfluency, characterized by pauses, blocks, prolongations and sound or syllable repetitions. It affects around 1% of the population, with potential detrimental effects on mental health and long-term employment. Accumulating evidence points to a genetic aetiology, yet gene–brain associations remain poorly understood due to a lack of MRI studies in affected families. Here we report the first neuroimaging study of developmental stuttering in a family with autosomal dominant inheritance of persistent stuttering. We studied a four-generation family, 16 family members were included in genotyping analysis. T1-weighted and diffusion-weighted MRI scans were conducted on seven family members (six male aged 9–63 years) with two age and sex matched controls without stuttering (n = 14). Using Freesurfer, we analysed cortical morphology (cortical thickness, surface area and local gyrification index) and basal ganglia volumes. White matter integrity in key speech and language tracts (i.e. frontal aslant tract and arcuate fasciculus) was also analysed using MRtrix and probabilistic tractography. We identified a significant age by group interaction effect for cortical thickness in the left hemisphere pars opercularis (Broca’s area). In affected family members this region failed to follow the typical trajectory of age-related thinning observed in controls. Surface area analysis revealed the middle frontal gyrus region was reduced bilaterally in the family (all cortical morphometry significance levels set at a vertex-wise threshold of P & 0.01, corrected for multiple comparisons). Both the left and right globus pallidus were larger in the family than in the control group (left P = 0.017 right P = 0.037), and a larger right globus pallidus was associated with more severe stuttering (rho = 0.86, P = 0.01). No white matter differences were identified. Genotyping identified novel loci on chromosomes 1 and 4 that map with the stuttering phenotype. Our findings denote disruption within the cortico-basal ganglia-thalamo-cortical network. The lack of typical development of these structures reflects the anatomical basis of the abnormal inhibitory control network between Broca’s area and the striatum underpinning stuttering in these in iduals. This is the first evidence of a neural phenotype in a family with an autosomal dominantly inherited stuttering.
Familial cortical dysplasia caused by mutation in the mammalian target of rapamycin regulator NPRL3
Publisher: Wiley
Date: 12-12-2016
DOI: 10.1002/ANA.24502
Abstract: We describe first cousin sibling pairs with focal epilepsy, one of each pair having focal cortical dysplasia (FCD) IIa. Linkage analysis and whole-exome sequencing identified a heterozygous germline frameshift mutation in the gene encoding nitrogen permease regulator-like 3 (NPRL3). NPRL3 is a component of GAP Activity Towards Rags 1, a negative regulator of the mammalian target of rapamycin complex 1 signaling pathway. Immunostaining of resected brain tissue demonstrated mammalian target of rapamycin activation. Screening of 52 unrelated in iduals with FCD identified 2 additional patients with FCDIIa and germline NPRL3 mutations. Similar to DEPDC5, NPRL3 mutations may be considered as causal variants in patients with FCD or magnetic resonance imaging-negative focal epilepsy.
Deficiency of 5-hydroxyisourate hydrolase causes hepatomegaly and hepatocellular carcinoma in mice
Publisher: Proceedings of the National Academy of Sciences
Date: 07-09-2010
Abstract: With the notable exception of humans, uric acid is degraded to (S)-allantoin in a biochemical pathway catalyzed by urate oxidase, 5-hydroxyisourate (HIU) hydrolase, and 2-oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline decarboxylase in most vertebrate species. A point mutation in the gene encoding mouse HIU hydrolase, Urah , that perturbed uric acid metabolism within the liver was discovered during a mutagenesis screen in mice. The predicted substitution of cysteine for tyrosine in a conserved helical region of the mutant-encoded HIU hydrolase resulted in undetectable protein expression. Mice homozygous for this mutation developed elevated platelet counts secondary to excess thrombopoietin production and hepatomegaly. The majority of homozygous mutant mice also developed hepatocellular carcinoma, and tumor development was accelerated by exposure to radiation. The development of hepatomegaly and liver tumors in mice lacking Urah suggests that uric acid metabolites may be toxic and that urate oxidase activity without HIU hydrolase function may affect liver growth and transformation. The absence of HIU hydrolase in humans predicts slowed metabolism of HIU after clinical administration of exogenous urate oxidase in conditions of uric acid-related pathology. The data suggest that prolonged urate oxidase therapy should be combined with careful assessment of toxicity associated with extrahepatic production of uric acid metabolites.
Heterozygous PNPT1 Variants Cause Spinocerebellar Ataxia Type 25
Publisher: Wiley
Date: 07-05-2022
DOI: 10.1002/ANA.26366
Abstract: Dominant spinocerebellar ataxias (SCA) are characterized by genetic heterogeneity. Some mapped and named loci remain without a causal gene identified. Here we applied next generation sequencing (NGS) to uncover the genetic etiology of the SCA25 locus . Whole‐exome and whole‐genome sequencing were performed in families linked to SCA25 , including the French family in which the SCA25 locus was originally mapped. Whole exome sequence data were interrogated in a cohort of 796 ataxia patients of unknown etiology. The SCA25 phenotype spans a slowly evolving sensory and cerebellar ataxia, in most cases attributed to ganglionopathy. A pathogenic variant causing exon skipping was identified in the gene encoding Polyribonucleotide Nucleotidyltransferase PNPase 1 ( PNPT1) located in the SCA25 linkage interval. A second splice variant in PNPT1 was detected in a large Australian family with a dominant ataxia also mapping to SCA25 . An additional nonsense variant was detected in an unrelated in idual with ataxia. Both nonsense and splice heterozygous variants result in premature stop codons, all located in the S1‐domain of PNPase. In addition, an elevated type I interferon response was observed in blood from all affected heterozygous carriers tested. PNPase notably prevents the abnormal accumulation of double‐stranded mtRNAs in the mitochondria and leakage into the cytoplasm, associated with triggering a type I interferon response. This study identifies PNPT1 as a new SCA gene, responsible for SCA25, and highlights biological links between alterations of mtRNA trafficking, interferonopathies and ataxia. ANN NEUROL 2022 :122–137
Common risk variants for epilepsy are enriched in families previously targeted for rare monogenic variant discovery
Publisher: Elsevier BV
Date: 07-2022
An intronic GAA repeat expansion in FGF14 causes the autosomal-dominant adult-onset ataxia SCA50/ATX-FGF14
Publisher: Elsevier BV
Date: 2221
An intronic GAA repeat expansion in FGF14 causes the autosomal-dominant adult-onset ataxia SCA27B/ATX-FGF14
Publisher: Elsevier BV
Date: 06-2023
Complete callosal agenesis, pontocerebellar hypoplasia, and axonal neuropathy due to AMPD2 loss
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 16-07-2015
Familial cortical dysplasia type IIA caused by a germline mutation in DEPDC5
Publisher: Wiley
Date: 12-03-2015
DOI: 10.1002/ACN3.191
Divergent amino acid and sphingolipid metabolism in patients with inherited neuro-retinal disease
Publisher: Cold Spring Harbor Laboratory
Date: 10-11-2022
DOI: 10.1101/2022.11.09.22281993
Abstract: The non-essential amino acids serine, glycine, and alanine, as well as erse sphingolipid species, are implicated in inherited neuro-retinal disorders and are metabolically linked by serine palmitoyltransferase (SPT), a key enzyme in membrane lipid biogenesis. To gain insights into the pathophysiological mechanisms linking these pathways to neuro-retinal diseases we performed a targeted metabolomic analysis of these pathways in sera from patients diagnosed with two metabolically intertwined diseases: macular telangiectasia type II (MacTel), hereditary sensory autonomic neuropathy type 1 (HSAN1), or both. In a cohort of participants, MacTel patients exhibited broad alterations of amino acids, including changes in serine, glycine, alanine, glutamate, and branched-chain amino acids reminiscent of diabetes. MacTel patients had elevated 1-deoxysphingolipids but reduced levels of complex sphingolipids in circulation. A mouse model indicates this depletion in complex sphingolipids can be driven by low dietary serine and glycine. HSAN1 patients exhibited elevated serine, lower alanine, and a reduction in canonical ceramides and sphingomyelins compared to controls. Those patients diagnosed with both HSAN1 and MacTel showed the most significant decrease in circulating sphingomyelins. These results highlight metabolic distinctions between these two diseases, emphasize the importance of membrane lipids in the progression of MacTel, and suggest distinct therapeutic approaches.
Mapping of the plasmodium chabaudi resistance locus char2
Publisher: American Society for Microbiology
Date: 10-2006
DOI: 10.1128/IAI.01690-05
Abstract: Animals congenic for the char2 host response locus to the murine malarial parasite Plasmodium chabaudi have been bred, and they demonstrated a phenotypic difference from the parental lines. These congenic lines have been crossed back to the parental line to generate recombinants across the congenic intervals. The recombinants were inbred, and the subcongenic intervals were fixed. These lines were then challenged with parasites and assessed as being either resistant or susceptible. From the analysis of many subcongenic lines, it has become obvious that there are at least two loci underlying the char2 locus and that both of these mediate resistance when the haplotype derives from the resistant C57BL/6 strain.
Detection and discovery of repeat expansions in ataxia enabled by next-generation sequencing: present and future
Publisher: Portland Press Ltd.
Date: 21-09-2023
DOI: 10.1042/ETLS20230018
Statistical haemoglobin thresholds to define anaemia across the lifecycle.
Publisher: Cold Spring Harbor Laboratory
Date: 25-05-2023
DOI: 10.1101/2023.05.22.23290129
Abstract: Detection of anaemia is critical for clinical medicine and public health. Current WHO values that define anaemia are statistical thresholds (5 th centile) set over 50 years ago, and are presently g/L in children 6-59 months, g/L in children 5-11 years, g/L in pregnant women, g/L in children 12-14 years of age, g/L in non-pregnant women, and g/L in men. Haemoglobin is sensitive to iron and other nutrient deficiencies, medical illness and inflammation, and is impacted by genetic conditions thus, careful exclusion of these conditions is crucial to obtain a healthy reference population. We identified data sources from which sufficient clinical and laboratory information was available to determine an apparently healthy reference s le. In iduals were excluded if they had any clinical or biochemical evidence of a condition that may diminish haemoglobin concentration. Discrete 5 th centiles were estimated along with two-sided 90% confidence intervals and estimates combined using a fixed-effect approach. Estimates for the 5 th centile of the healthy reference population in children were similar between sexes. Thresholds in children 6-23 months were 104.4g/L [90% CI 103.5, 105.3] in children 24-59 months were 110.2g/L [109.5, 110.9] and in children 5-11 years were 114.1g/L [113.2, 115.0]. Thresholds erged by sex in adolescents and adults. In females and males 12-17 years, thresholds were 122.2g/L [121.3, 123.1] and 128.2 [126.4, 130.0], respectively. In adults 18-65 years, thresholds were 119.7g/L [119.1, 120.3] in non-pregnant females and 134.9g/L [134.2, 135.6] in males. Limited analyses indicated 5 th centiles in first-trimester pregnancy of 110.3g/L [109.5, 111.0] and 105.9g/L [104.0, 107.7] in the second trimester. All thresholds were robust to variations in definitions and analysis models. Using multiple datasets comprising Asian, African, and European ancestries, we did not identify novel high prevalence genetic variants that influence haemoglobin concentration, other than variants in genes known to cause important clinical disease, suggesting non-clinical genetic factors do not influence the 5 th centile between ancestries. Our results directly inform WHO guideline development and provide a platform for global harmonisation of laboratory, clinical and public health haemoglobin thresholds.
Kufs disease, the major adult form of neuronal ceroid lipofuscinosis, caused by mutations in cln6
Publisher: Elsevier BV
Date: 05-2011
A Cav3.2 T-type calcium channel point mutation has splice-variant-specific effects on function and segregates with seizure expression in a polygenic rat model of absence epilepsy
Publisher: Society for Neuroscience
Date: 14-01-2009
DOI: 10.1523/JNEUROSCI.5295-08.2009
Abstract: Low-voltage-activated, or T-type, calcium (Ca 2+ ) channels are believed to play an essential role in the generation of absence seizures in the idiopathic generalized epilepsies (IGEs). We describe a homozygous, missense, single nucleotide (G to C) mutation in the Ca v 3.2 T-type Ca 2+ channel gene ( Cacna1h ) in the genetic absence epilepsy rats from Strasbourg (GAERS) model of IGE. The GAERS Ca v 3.2 mutation ( gcm ) produces an arginine to proline (R1584P) substitution in exon 24 of Cacna1h , encoding a portion of the III–IV linker region in Ca v 3.2. gcm segregates codominantly with the number of seizures and time in seizure activity in progeny of an F1 intercross. We have further identified two major thalamic Cacna1h splice variants, either with or without exon 25. gcm introduced into the splice variants acts “epistatically,” requiring the presence of exon 25 to produce significantly faster recovery from channel inactivation and greater charge transference during high-frequency bursts. This gain-of-function mutation, the first reported in the GAERS polygenic animal model, has a novel mechanism of action, being dependent on exonic splicing for its functional consequences to be expressed.
Guiding and interpreting brain network classification with transcriptional data
Publisher: Cold Spring Harbor Laboratory
Date: 16-05-2020
DOI: 10.1101/2020.05.15.099028
Abstract: The investigation of brain networks has yielded many insights that have helped to characterise many neurological and psychiatric disorders. In particular, network classification of functional magnetic resonance imaging (fMRI) data is an important tool for the identification of prognostic and diagnostic biomarkers of brain connectivity disorders such as schizophrenia and depression. However, existing generic network classification methods provide no direct information on the underlying molecular mechanisms of the selected functional connectivity features when applied to fMRI data. To address this, we propose a novel fMRI network classification method that incor-porates brain transcriptional data using a user-specified gene set collection (GSC) to construct feature groups for use in classification of brain connectivity data. The use of GSCs are an opportunity to incorporate knowledge of potential molecular mechanisms which may be associated with a disease. The inclusion of transcriptional data yields improved prediction accuracy on publicly available schizophrenia fMRI data for several of the GSCs we consider. We also introduce a post-hoc interpretation framework to provide transcriptional-data-guided biological interpretations for discriminative functional connectivity features identified by existing fMRI network classification methods.
An α-E-catenin (CTNNA1) mutation in hereditary diffuse gastric cancer
Publisher: Wiley
Date: 15-02-2013
DOI: 10.1002/PATH.4152
Abstract: Diffuse gastric cancers typically present as late-stage tumours and, as a result, the 5 year survival rate is poor. Some gastric cancers are hereditary and these tend to be of the diffuse type 30-40% of hereditary diffuse gastric cancers (HDGCs) can be explained by defective germline alleles of E-cadherin (CDH1), but for the remaining families the factors driving susceptibility remain unknown. We had access to a large HDGC pedigree with no obvious mutation in CDH1, and applied exome sequencing to identify new genes involved in gastric cancer. We identified a germline truncating allele of α-E-catenin (CTNNA1) that was present in two family members with invasive diffuse gastric cancer and four in which intramucosal signet ring cells were detected as part of endoscopic surveillance. The remaining CTNNA1 allele was silenced in the two diffuse gastric cancers from the family that were available for screening, and this was also true for signet ring cells identified in endoscopic biopsies. Since α-E-catenin functions in the same complex as E-cadherin, our results call attention to the broader signalling network surrounding these proteins in HDGC. We also detected somatic mutations in one tumour and found substantial overlap with genes mutated in sporadic gastric cancer, including PIK3CA, ARID1A, MED12 and MED23.
X chromosome association testing in genome wide association studies
Publisher: Wiley
Date: 04-08-2011
DOI: 10.1002/GEPI.20616
Abstract: Genome wide association studies (GWAS) have revealed many fascinating insights into complex diseases even from simple, single-marker statistical tests. Most of these tests are designed for testing of associations between a phenotype and an autosomal genotype and are therefore not applicable to X chromosome data. Testing for association on the X chromosome raises unique challenges that have motivated the development of X-specific statistical tests in the literature. However, to date there has been no study of these methods under a wide range of realistic study designs, allele frequencies and disease models to assess the size and power of each test. To address this, we have performed an extensive simulation study to investigate the effects of the sex ratios in the case and control cohorts, as well as the allele frequencies, on the size and power of eight test statistics under three different disease models that each account for X-inactivation. We show that existing, but under-used, methods that make use of both male and female data are uniformly more powerful than popular methods that make use of only female data. In particular, we show that Clayton's one degree of freedom statistic [Clayton, 2008] is robust and powerful across a wide range of realistic simulation parameters. Our results provide guidance on selecting the most appropriate test statistic to analyse X chromosome data from GWAS and show that much power can be gained by a more careful analysis of X chromosome GWAS data.
Identical by descent L1CAM mutation in two apparently unrelated families with intellectual disability without L1 syndrome
Publisher: Elsevier BV
Date: 06-2015
DOI: 10.1016/J.EJMG.2015.04.004
Abstract: Mutations in the L1 Cell Adhesion Molecule (L1CAM) gene (MIM#308840) cause a variety of X-linked recessive neurological disorders collectively called L1 syndrome. Using massively parallel sequencing (MPS) of the X-chromosome exome, we identified a novel missense variant in L1CAM in two Caucasian families with mild-moderate intellectual disability without obvious L1 syndrome features. These families were not known to be related. SNP data extracted from MPS identified a 5.6 cM tract of identity by descent (IBD), encompassing the L1CAM gene, between the DNA of the two probands. This cannot be explained by chance alone and strongly implies that the two families are related. It also suggests that the L1CAM (NM_000425.3, c.604G > A, p.D202N) variant is pathogenic. This report also demonstrates the usefulness of additional information, which can be extracted from exome sequencing data.
Identification and analysis of error types in high-throughput genotyping
Publisher: Elsevier BV
Date: 09-2000
DOI: 10.1086/303048
Recent advances in the detection of repeat expansions with short-read next-generation sequencing [version 1; referees: 3 approved]
Publisher: F1000 Research Ltd
Date: 13-06-2018
DOI: 10.12688/F1000RESEARCH.13980.1
Abstract: Short tandem repeats (STRs), also known as microsatellites, are commonly defined as consisting of tandemly repeated nucleotide motifs of 2–6 base pairs in length. STRs appear throughout the human genome, and about 239,000 are documented in the Simple Repeats Track available from the UCSC (University of California, Santa Cruz) genome browser. STRs vary in size, producing highly polymorphic markers commonly used as genetic markers. A small fraction of STRs (about 30 loci) have been associated with human disease whereby one or both alleles exceed an STR-specific threshold in size, leading to disease. Detection of repeat expansions is currently performed with polymerase chain reaction–based assays or with Southern blots for large expansions. The tests are expensive and time-consuming and are not always conclusive, leading to lengthy diagnostic journeys for patients, potentially including missed diagnoses. The advent of whole exome and whole genome sequencing has identified the genetic cause of many genetic disorders however, analysis pipelines are focused primarily on the detection of short nucleotide variations and short insertions and deletions (indels). Until recently, repeat expansions, with the exception of the smallest expansion (SCA6), were not detectable in next-generation short-read sequencing datasets and would have been ignored in most analyses. In the last two years, four analysis methods with accompanying software (ExpansionHunter, exSTRa, STRetch, and TREDPARSE) have been released. Although a comprehensive comparative analysis of the performance of these methods across all known repeat expansions is still lacking, it is clear that these methods are a valuable addition to any existing analysis pipeline. Here, we detail how to assess short-read data for evidence of expansions, reviewing all four methods and outlining their strengths and weaknesses. Implementation of these methods should lead to increased diagnostic yield of repeat expansion disorders for known STR loci and has the potential to detect novel repeat expansions.
dtangle: Accurate and fast cell-type deconvolution
Publisher: Cold Spring Harbor Laboratory
Date: 27-03-2018
DOI: 10.1101/290262
Abstract: Understanding cell type composition is important to understanding many biological processes. Furthermore, in gene expression studies cell type composition can confound differential expression analysis (DEA). To aid understanding cell type composition, methods of estimating (deconvolving) cell type proportions from gene expression data have been developed. We propose dtangle, a new cell-type deconvolution method. dtangle works on a range of DNA microarray and bulk RNA-seq platforms. It estimates cell-type proportions using publicly available, often cross-platform, reference data. To comprehensively evaluate dtangle, we assemble ten benchmark data sets. Here, dtangle is competitive with published deconvolution methods, is robust to selection of tuning parameters and is quicker than other methods. As a case study, we investigate the human immune response to Lyme disease. dtangle’s estimates reveal a temporal trend consistent with previous findings and are important covariates for DEA across disease status. dtangle is on CRAN ( ackage=dtangle ) or github ( dtangle.github.io ). gjhunt@umich.edu
Systematic noise degrades gene co-expression signals but can be corrected
Publisher: Springer Science and Business Media LLC
Date: 24-09-2015
Plasmodium vivax Populations Are More Genetically Diverse and Less Structured than Sympatric Plasmodium falciparum Populations
Publisher: Public Library of Science (PLoS)
Date: 15-04-2015
Young-onset dementia diagnosis, management and care
Publisher: Wiley
Date: 03-06-2023
DOI: 10.5694/MJA2.51996
Diagnosis and misdiagnosis of adult neuronal ceroid lipofuscinosis (Kufs disease)
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 13-07-2016
WWOX developmental and epileptic encephalopathy: Understanding the epileptology and the mortality risk
Publisher: Wiley
Date: 04-10-2022
DOI: 10.1111/EPI.17542
Abstract: WWOX is an autosomal recessive cause of early infantile developmental and epileptic encephalopathy ( WWOX ‐DEE), also known as WOREE ( WWOX ‐related epileptic encephalopathy). We analyzed the epileptology and imaging features of WWOX ‐DEE, and investigated genotype–phenotype correlations, particularly with regard to survival. We studied 13 patients from 12 families with WWOX ‐DEE. Information regarding seizure semiology, comorbidities, facial dysmorphisms, and disease outcome were collected. Electroencephalographic (EEG) and brain magnetic resonance imaging (MRI) data were analyzed. Pathogenic WWOX variants from our cohort and the literature were coded as either null or missense, allowing in iduals to be classified into one of three genotype classes: (1) null/null, (2) null/missense, (3) missense/missense. Differences in survival outcome were estimated using the Kaplan–Meier method. All patients experienced multiple seizure types (median onset = 5 weeks, range = 1 day–10 months), the most frequent being focal (85%), epileptic spasms (77%), and tonic seizures (69%). Ictal EEG recordings in six of 13 patients showed tonic ( n = 5), myoclonic ( n = 2), epileptic spasms ( n = 2), focal ( n = 1), and migrating focal ( n = 1) seizures. Interictal EEGs demonstrated slow background activity with multifocal discharges, predominantly over frontal or temporo‐occipital regions. Eleven of 13 patients had a movement disorder, most frequently dystonia. Brain MRIs revealed severe frontotemporal, hippoc al, and optic atrophy, thin corpus callosum, and white matter signal abnormalities. Pathogenic variants were located throughout WWOX and comprised both missense and null changes including five copy number variants (four deletions, one duplication). Survival analyses showed that patients with two null variants are at higher mortality risk ( p ‐value = .0085, log‐rank test). Biallelic WWOX pathogenic variants cause an early infantile developmental and epileptic encephalopathy syndrome. The most common seizure types are focal seizures and epileptic spasms. Mortality risk is associated with mutation type patients with biallelic null WWOX pathogenic variants have significantly lower survival probability compared to those carrying at least one presumed hypomorphic missense pathogenic variant.
Clinical impact of whole-genome sequencing in patients with early-onset dementia
Publisher: BMJ
Date: 29-07-2022
Abstract: In the clinical setting, identification of the genetic cause in patients with early-onset dementia (EOD) is challenging due to multiple types of genetic tests required to arrive at a diagnosis. Whole-genome sequencing (WGS) has the potential to serve as a single diagnostic platform, due to its superior ability to detect common, rare and structural genetic variation. WGS analysis was performed in 50 patients with EOD. Point mutations, small insertions/deletions, as well as structural variants (SVs) and short tandem repeats (STRs), were analysed. An Alzheimer’s disease (AD)-related polygenic risk score (PRS) was calculated in patients with AD. Clinical genetic diagnosis was achieved in 7 of 50 (14%) of the patients, with a further 8 patients (16%) found to have established risk factors which may have contributed to their EOD. Two pathogenic variants were identified through SV analysis. No expanded STRs were found in this study cohort, but a blinded analysis with a positive control identified a C9orf72 expansion accurately. Approximately 37% (7 of 19) of patients with AD had a PRS equivalent to th percentile risk. WGS acts as a single genetic test to identify different types of clinically relevant genetic variations in patients with EOD. WGS, if used as a first-line clinical diagnostic test, has the potential to increase the diagnostic yield and reduce time to diagnosis for EOD.
Multi-omic spatial effects on high-resolution AI-derived retinal thickness
Publisher: Cold Spring Harbor Laboratory
Date: 02-08-2023
DOI: 10.1101/2023.07.31.23293176
Abstract: Retinal thickness is a marker of retinal health and more broadly, is seen as a promising biomarker for many systemic diseases. Retinal thickness measurements are procured from optical coherence tomography (OCT) as part of routine clinical eyecare. We processed the UK Biobank OCT images using a convolutional neural network to produce fine-scale retinal thickness measurements across ,000 points in the macula, the part of the retina responsible for human central vision. The macula is disproportionately affected by high disease burden retinal disorders such as age-related macular degeneration and diabetic retinopathy, which both involve metabolic dysregulation. Analysis of common genomic variants, metabolomic, blood and immune biomarkers, ICD10 codes and polygenic risk scores across a fine-scale macular thickness grid, reveals multiple novel genetic loci-including four on the X chromosome retinal thinning associated with many systemic disorders including multiple sclerosis and multiple associations to correlated metabolites that cluster spatially in the retina. We highlight parafoveal thickness to be particularly susceptible to systemic insults. These results demonstrate the gains in discovery power and resolution achievable with AI-leveraged analysis. Results are accessible using a bespoke web interface that gives full control to pursue findings.
Increasingly inbred and fragmented populations of Plasmodium vivax with declining transmission
Publisher: Cold Spring Harbor Laboratory
Date: 15-01-2017
DOI: 10.1101/100610
Abstract: The human malaria parasite Plasmodium vivax is resistant to malaria control strategies maintaining high genetic ersity even when transmission is low. To investigate whether declining P. vivax transmission leads to increasing P. vivax population structure that would facilitate elimination, we genotyped s les from a wide range of transmission intensities and spatial scales in the Southwest Pacific, including two time points at one site (Tetere, Solomon Islands) during intensified control. Analysis of 887 P. vivax microsatellite haplotypes from hyperendemic Papua New Guinea (PNG, n = 443), meso-hyperendemic Solomon Islands (n= 420), and hypoendemic Vanuatu (n=24) revealed increasing population structure and multilocus linkage disequilibrium and a modest decline in ersity as transmission decreases over space and time. In Solomon Islands, which has had sustained control efforts for 20 years, and Vanuatu, which has experienced sustained low transmission for many years, significant population structure was observed at different spatial scales. We conclude that control efforts will eventually impact P. vivax population structure and with sustained pressure, populations may eventually fragment into a limited number of clustered foci that could be targeted for elimination.
Population-level genome-wide STR discovery and validation for population structure and genetic diversity assessment of Plasmodium species
Publisher: Public Library of Science (PLoS)
Date: 10-01-2022
DOI: 10.1371/JOURNAL.PGEN.1009604
Abstract: Short tandem repeats (STRs) are highly informative genetic markers that have been used extensively in population genetics analysis. They are an important source of genetic ersity and can also have functional impact. Despite the availability of bioinformatic methods that permit large-scale genome-wide genotyping of STRs from whole genome sequencing data, they have not previously been applied to sequencing data from large collections of malaria parasite field s les. Here, we have genotyped STRs using HipSTR in more than 3,000 Plasmodium falciparum and 174 Plasmodium vivax published whole-genome sequence data from s les collected across the globe. High levels of noise and variability in the resultant callset necessitated the development of a novel method for quality control of STR genotype calls. A set of high-quality STR loci (6,768 from P . falciparum and 3,496 from P . vivax ) were used to study Plasmodium genetic ersity, population structures and genomic signatures of selection and these were compared to genome-wide single nucleotide polymorphism (SNP) genotyping data. In addition, the genome-wide information about genetic variation and other characteristics of STRs in P . falciparum and P . vivax have been available in an interactive web-based R Shiny application PlasmoSTR ( ahlolab/PlasmoSTR ).
Comparison of clustering tools in R for medium-sized 10x genomics single-cell RNA-sequencing data [version 1; referees: 1 approved, 2 approved with reservations]
Publisher: F1000 Research Ltd
Date: 15-08-2018
DOI: 10.12688/F1000RESEARCH.15809.1
Abstract: Background: The commercially available 10x Genomics protocol to generate droplet-based single-cell RNA-seq (scRNA-seq) data is enjoying growing popularity among researchers. Fundamental to the analysis of such scRNA-seq data is the ability to cluster similar or same cells into non-overlapping groups. Many competing methods have been proposed for this task, but there is currently little guidance with regards to which method to use. Methods: Here we use one gold standard 10x Genomics dataset, generated from the mixture of three cell lines, as well as three silver standard 10x Genomics datasets generated from peripheral blood mononuclear cells to examine not only the accuracy but also robustness of a dozen methods. Results: We found that some methods, including Seurat and Cell Ranger, outperform other methods, although performance seems to be dependent on the complexity of the studied system. Furthermore, we found that solutions produced by different methods have little in common with each other. Conclusions: In light of this, we conclude that the choice of clustering tool crucially determines interpretation of scRNA-seq data generated by 10x Genomics. Hence practitioners and consumers should remain vigilant about the outcome of 10x Genomics scRNA-seq analysis.
SCN1A clinical spectrum includes the self-limited focal epilepsies of childhood
Publisher: Elsevier BV
Date: 03-2017
DOI: 10.1016/J.EPLEPSYRES.2017.01.012
Abstract: Amongst autosomal dominant genetic epilepsy with febrile seizures plus (GEFS+) families, SCN1A variants are the most common genetic cause. Initially regarded as a generalized form of epilepsy, the GEFS+ spectrum is now known to include some focal epilepsies, but it is generally not conceptualized as extending to the self-limited focal epilepsies of childhood, such as Panayiotopoulos syndrome. There are, however, three reports of SCN1A variants in Panayiotopoulos syndrome. We describe the variable clinical phenotypes that include the self-limited focal epilepsies of childhood, present in a large GEFS+ family, segregating a heterozygous SCN1A missense variant. Electro-clinical details on all putatively affected family members were sought and blood s les were taken for genetic analysis. Two in iduals were chosen for SCN1A testing. All 26 exons and exon-intron junctions were lified, sequenced and analyzed. This was followed by pedigree segregation analysis of the variant identified. A pathogenic heterozygous SCN1A (c.2624C>A p.Thr875Lys) variant was identified. Sixteen of the 18 variant positive family members were affected (88% penetrance): 8 with febrile seizures, 2 febrile seizures plus, 1 unclassified seizures and 5 with self-limited focal epilepsy of childhood. Of these, one was diagnosed with atypical childhood epilepsy with centrotemporal spikes and four with Panayiotopoulos syndrome. By characterizing the heterogeneous clinical phenotypes in a large, SCN1A mutation positive GEFS+ family, we conclude that the GEFS+ spectrum can extend to the self-limited focal epilepsies of childhood, including Panayiotopoulos syndrome, and in turn highlight the complex genotype-phenotype correlations associated with SCN1A-related epilepsies.
Familial early onset Parkinson's disease caused by a homozygous frameshift variant in PARK7: Clinical features and literature update
Publisher: Elsevier BV
Date: 07-2019
DOI: 10.1016/J.PARKRELDIS.2019.03.013
Abstract: Bi-allelic mutations in PARK7 are a rare cause of autosomal recessive early onset Parkinson's disease (EO-PD). To date, 30 in iduals harbouring 20 unique causative variants have been described. Understanding of the spectrum of clinical features and natural history of PARK7 mediated EO-PD remain limited. We studied a family with three offspring, two of whom were affected with EO-PD. Family members underwent detailed clinical examination and DNA s les from both affected in iduals and parents were analysed by exome sequencing. Two brothers of Iranian descent presented at age 29 years with Parkinsonism associated with high-pitched voice and hypomimia. The brothers were followed over a six and fifteen-year period and displayed typical levodopa responsive slowly-progressive Parkinsonism. A novel homozygous frameshift mutation in PARK7 [NM_007262.4:c.90dupG, p(Ile31Aspfs*2)] was identified. Here we report the clinical presentation and progression of EO-PD in brothers with a novel pathogenic PARK7 variant. We expand the clinical phenotype and provide an update of clinical and pathological features of the disorder.
A founder event causing a dominant childhood epilepsy survives 800 years through weak selective pressure
Publisher: Elsevier BV
Date: 11-2022
Comparison of clustering tools in R for medium-sized 10x Genomics single-cell RNA-sequencing data
Publisher: F1000 Research Ltd
Date: 19-12-2018
DOI: 10.12688/F1000RESEARCH.15809.2
Abstract: Background: The commercially available 10x Genomics protocol to generate droplet-based single cell RNA-seq (scRNA-seq) data is enjoying growing popularity among researchers. Fundamental to the analysis of such scRNA-seq data is the ability to cluster similar or same cells into non-overlapping groups. Many competing methods have been proposed for this task, but there is currently little guidance with regards to which method to use. Methods: Here we use one gold standard 10x Genomics dataset, generated from the mixture of three cell lines, as well as multiple silver standard 10x Genomics datasets generated from peripheral blood mononuclear cells to examine not only the accuracy but also running time and robustness of a dozen methods. Results: We found that Seurat outperformed other methods, although performance seems to be dependent on many factors, including the complexity of the studied system. Furthermore, we found that solutions produced by different methods have little in common with each other. Conclusions: In light of this we conclude that the choice of clustering tool crucially determines interpretation of scRNA-seq data generated by 10x Genomics. Hence practitioners and consumers should remain vigilant about the outcome of 10x Genomics scRNA-seq analysis.
Mutations in TMC1 are a common cause of DFNB7/11 hearing loss in the Iranian population
Publisher: SAGE Publications
Date: 12-2010
DOI: 10.1177/000348941011901207
Abstract: We investigated the cause of autosomal recessive nonsyndromic hearing loss (ARNSHL) that segregated in 2 consanguineous Iranian families. Otologic and audiometric examinations were performed on affected members of each family. Genome-wide parametric multipoint linkage mapping using a recessive model was performed with Affymetrix 50K GeneChips or short tandem repeat polymorphisms. Direct sequencing was used to confirm the causative mutation in each family. In 2 Iranian families, L-1651 and L-8600606, with ARNSHL that mapped to the DFNB7/11 locus, homozygosity for a reported splice site mutation (c.776+1G A), and a novel deletion (c.1589_1590delCT p.S530) were identified in the TMC1 gene, respectively. Consistent with the previously reported phenotype in DFNB7/11 families, the 2 Iranian families had segregated congenital, profound hearing impairment. However, in family L-1651, one affected family member (IV:3) has milder hearing impairment than expected, suggesting a potential genetic modifier effect. These results indicate that DFNB7/11 is a common form of genetic hearing loss in Iran, because this population is the source of 6 of the 29 TMC1 mutations reported worldwide.
Mutations in SPRTN cause early onset hepatocellular carcinoma, genomic instability and progeroid features
Publisher: Springer Science and Business Media LLC
Date: 25-10-0001
DOI: 10.1038/NG.3103
A tissue-specific marker of Ecdysozoa
Publisher: Springer Science and Business Media LLC
Date: 09-2001
Abstract: Over the past few years, molecular studies of phylogeny have challenged the traditional view of evolutionary relationships among protostomian animal phyla. Based on analysis of 18S ribosomal RNA gene sequences, it has been suggested that some traditional groups, like the articulata and the pseudocoelomata, should be completely abandoned and that instead the protostomians should be split into two major clades: the Ecdysozoa and the Lophotrochozoa. However, this new molecular phylogeny still awaits confirmation by independent methods. In this study, we present a cytological feature that supports the new classification. The carbohydrate epitope that is recognised by antisera against the plant glycoprotein horseradish peroxidase (HRP) is known to be selectively expressed by membrane proteins on the surface of neural tissue in insects. We found that the major ecdysozoan phyla show neural expression of HRP immunoreactivity, which is completely absent in the nervous tissue of lophotrochozoans, deuterostomians, and cnidarians. This suggests that the presence of anti-HRP-reactive glycoproteins in neural tissue is an ecdysozoan autapomorphy.
Investigating and correcting plasma DNA sequencing coverage bias to enhance aneuploidy discovery
Publisher: Public Library of Science (PLoS)
Date: 29-01-2014
Heterozygous mutations in HSD17B4 cause juvenile peroxisomal D-bifunctional protein deficiency
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 18-10-2016
Fine-Mapping the Genetic Association of the Major Histocompatibility Complex in Multiple Sclerosis: HLA and Non-HLA Effects
Publisher: Public Library of Science (PLoS)
Date: 21-11-2013
GNE myopathy in Roma patients homozygous for the p.I618T founder mutation
Publisher: Elsevier BV
Date: 09-2015
DOI: 10.1016/J.NMD.2015.07.004
Abstract: GNE myopathy is an autosomal-recessive disorder caused by mutations in the GNE gene, encoding the key enzyme in the sialic acid biosynthetic pathway, UDP-N-acetylglucosamine 2-epimerase/N-acetyl mannosamine kinase. We studied 50 Bulgarian Roma patients homozygous for p.I618T, an ancient founder mutation in the kinase domain of the GNE gene, dating before the Gypsy exodus from North West India. The clinical features in the Bulgarian GNE group can be described with disease onset mostly in the third decade, but in in idual cases, onset was as early as 10 years of age. The majority of patients had foot drop as the first symptom, but three patients developed hand weakness first. Muscle weakness was early and severe for the tibialis anterior, and minimal or late for quadriceps femoris, and respiratory muscles were only subclinically affected even in the advanced stages of the disease. During a 15-year follow-up period, 32 patients became non-ambulant. The average period between disease onset and loss of ambulation was 10.34 ± 4.31 years, ranging from 3 to 20 years. Our analysis of affected sib pairs suggested a possible role of genetic modifying factors, accounting for significant variation in disease severity.
A novel splice site mutation in EYA4 causes DFNA10 hearing loss (Am J Med Genet 143(14): 1599–1604)
Publisher: Wiley
Date: 2008
DOI: 10.1002/AJMG.A.32134
Whole-transcriptome RNA editing analysis in single cortical neurons links locus 15q11 with psychiatric illness
Publisher: Cold Spring Harbor Laboratory
Date: 14-11-2019
DOI: 10.1101/840892
Abstract: Conversion of adenosine to inosine in RNA by ADAR enzymes occurs at thousands of sites in the human transcriptome, and is essential for healthy brain development. This ‘RNA editing’ process is dysregulated in many neuropsychiatric diseases, but is little understood at the level of in idual neurons. We quantified RNA editing sites in full-length capture nuclear transcriptomes of 3055 neurons from six cortical regions of a neurotypical post-mortem female donor. Putative editing sites were intersected with sites in bulk human tissue transcriptomes including healthy and neuropsychiatric brain tissue, and sites identified in single nuclei from unrelated brain donors. Differential editing between cell types and cortical regions, and in idual sites and genes therein, was quantified using linear models. Associations between gene expression and editing were also tested. We identified 41,930 RNA editing sites with robust read coverage in at least ten neuronal nuclei. Most sites were located within Alu repeats in introns or 3’ UTRs, and approximately 80% were catalogued in published RNA editing databases. We identified 9285 putative novel RNA editing sites, 29% of which were also detectable neuronal transcriptomes from unrelated donors. Inhibitory neurons showed higher overall transcriptome editing than excitatory neurons. Among the strongest correlates of global editing rates were snoRNAs from the SNORD115 and SNORD116 cluster (15q11), known to modulate serotonin receptor processing and to colocalize with ADAR2. We identified 29 genes preferentially edited in excitatory neurons and 44 genes edited more heavily in inhibitory neurons including RBFOX1, its target genes and small nucleolar RNA-associated genes in the autism-associated Prader-Willi locus 15q11. These results provide cell-type and spatial context for 1730 and 910 sites that are also edited in the brains of schizophrenic and autistic patients respectively, and a reference for future studies of RNA editing in single brain cells from these cohorts. RNA editing, including thousands of previously unreported sites, is robustly detectable in single neuronal nuclei, where gene editing differences are stronger between cell subtypes than between cortical regions. Insufficient editing of ASD-related genes in inhibitory neurons may manifest in the specific perturbation of these cells in autism.
Erratum: Recessive Spondylocarpotarsal Synostosis Syndrome Due to Compound Heterozygosity for Variants in MYH3 (The American Journal of Human Genetics (2018) 102(6) (1115–1125), (S000292971830140X), (10.1016/j.ajhg.2018.04.008))
Publisher: Elsevier BV
Date: 09-2019
Whole exome sequencing combined with linkage analysis identifies a novel 3 bp deletion in NR5A1
Publisher: Springer Science and Business Media LLC
Date: 06-08-2015
Small intragenic deletion in FOXP2 associated with childhood apraxia of speech and dysarthria
Publisher: Wiley
Date: 05-08-2013
DOI: 10.1002/AJMG.A.36055
Abstract: Relatively little is known about the neurobiological basis of speech disorders although genetic determinants are increasingly recognized. The first gene for primary speech disorder was FOXP2, identified in a large, informative family with verbal and oral dyspraxia. Subsequently, many de novo and familial cases with a severe speech disorder associated with FOXP2 mutations have been reported. These mutations include sequencing alterations, translocations, uniparental disomy, and genomic copy number variants. We studied eight probands with speech disorder and their families. Family members were phenotyped using a comprehensive assessment of speech, oral motor function, language, literacy skills, and cognition. Coding regions of FOXP2 were screened to identify novel variants. Segregation of the variant was determined in the probands' families. Variants were identified in two probands. One child with severe motor speech disorder had a small de novo intragenic FOXP2 deletion. His phenotype included features of childhood apraxia of speech and dysarthria, oral motor dyspraxia, receptive and expressive language disorder, and literacy difficulties. The other variant was found in a family in two of three family members with stuttering, and also in the mother with oral motor impairment. This variant was considered a benign polymorphism as it was predicted to be non-pathogenic with in silico tools and found in database controls. This is the first report of a small intragenic deletion of FOXP2 that is likely to be the cause of severe motor speech disorder associated with language and literacy problems.
UKB.COVID19: an R package for UK Biobank COVID-19 data processing and analysis
Publisher: F1000 Research Ltd
Date: 19-08-2021
DOI: 10.12688/F1000RESEARCH.55370.1
Abstract: COVID-19 caused by SARS-CoV-2 has resulted in a global pandemic with a rapidly developing global health and economic crisis. Variations in the disease have been observed and have been associated with the genomic sequence of either the human host or the pathogen. Worldwide scientists scrambled initially to recruit patient cohorts to try and identify risk factors. A resource that presented itself early on was the UK Biobank (UKBB), which is investigating the respective contributions of genetic predisposition and environmental exposure to the development of disease. To enable COVID-19 studies, UKBB is now receiving COVID-19 test data for their participants every two weeks. In addition, UKBB is delivering more frequent updates of death and hospital inpatient data (including critical care admissions) on the UKBB Data Portal. This frequently changing dataset requires a tool that can rapidly process and analyse up-to-date data. We developed an R package specifically for the UKBB COVID-19 data, which summarises COVID-19 test results, performs association tests between COVID-19 susceptibility/severity and potential risk factors such as age, sex, blood type, comorbidities and generates input files for genome-wide association studies (GWAS). By applying the R package to data released in April 2021, we found that age, body mass index, socioeconomic status and smoking are positively associated with COVID-19 susceptibility, severity, and mortality. Males are at a higher risk of COVID-19 infection than females. People staying in aged care homes have a higher chance of being exposed to SARS-CoV-2. By performing GWAS, we replicated the 3p21.31 genetic finding for COVID-19 susceptibility and severity. The ability to iteratively perform such analyses is highly relevant since the UKBB data is updated frequently. As a caveat, users must arrange their own access to the UKBB data to use the R package.
UKB.COVID19: an R package for UK Biobank COVID-19 data processing and analysis
Publisher: F1000 Research Ltd
Date: 18-05-2022
DOI: 10.12688/F1000RESEARCH.55370.2
Abstract: COVID-19 caused by SARS-CoV-2 has resulted in a global pandemic with a rapidly developing global health and economic crisis. Variations in the disease have been observed and have been associated with the genomic sequence of either the human host or the pathogen. Worldwide scientists scrambled initially to recruit patient cohorts to try and identify risk factors. A resource that presented itself early on was the UK Biobank (UKBB), which is investigating the respective contributions of genetic predisposition and environmental exposure to the development of disease. To enable COVID-19 studies, UKBB is now receiving COVID-19 test data for their participants every two weeks. In addition, UKBB is delivering more frequent updates of death and hospital inpatient data (including critical care admissions) on the UKBB Data Portal. This frequently changing dataset requires a tool that can rapidly process and analyse up-to-date data. We developed an R package specifically for the UKBB COVID-19 data, which summarises COVID-19 test results, performs association tests between COVID-19 susceptibility/severity and potential risk factors such as age, sex, blood type, comorbidities and generates input files for genome-wide association studies (GWAS). By applying the R package to data released in April 2021, we found that age, body mass index, socioeconomic status and smoking are positively associated with COVID-19 susceptibility, severity, and mortality. Males are at a higher risk of COVID-19 infection than females. People staying in aged care homes have a higher chance of being exposed to SARS-CoV-2. By performing GWAS, we replicated the 3p21.31 genetic finding for COVID-19 susceptibility and severity. The ability to iteratively perform such analyses is highly relevant since the UKBB data is updated frequently. As a caveat, users must arrange their own access to the UKBB data to use the R package.
Contribution of rare genetic variants to drug response in absence epilepsy
Publisher: Elsevier BV
Date: 02-2021
DOI: 10.1016/J.EPLEPSYRES.2020.106537
Abstract: We investigated the possible significance of rare genetic variants to response to valproic acid (VPA) and ethosuximide (ETX) in patients with absence epilepsy. Our primary hypothesis was that rare CACNA1H variants are more frequent in ETX-non-responsive patients compared to ETX-responsive. Our secondary hypothesis was that rare variants in GABA-receptor genes are more frequent in VPA-non-responsive patients compared to VPA-responsive. We recruited patients with absence epilepsy treated with both VPA and ETX, and performed whole exome sequencing in order to investigate the potential role of rare variants in CACNA1H, other voltage-gated calcium channel (VGCC) genes, or GABA-receptor genes in predicting response to ETX or VPA. Sixty-two patients were included 12 were ETX-responsive, 14 VPA-responsive, and 36 did not have a clear positive response to either medication. We did not find significant enrichment inCACNA1H rare variants in ETX-responsive patients (odds ratio 3.43 0.43-27.65 p = 0.20), nor was there enrichment for other VGCC genes. No significant enrichment of GABA-receptor gene rare variants was seen for VPA-non-responsive patients versus VPA-responsive. We found enrichment of rare GABA-receptor variants in our absence cohort compared to controls (odds ratio 3.82 1.68-8.69). There was no difference in frequency of CACNA1H rs61734410 and CACNA1I rs3747178 polymorphisms between ETX-responsive and ETX-non-responsive groups these polymorphisms have previously been reported to predict lack of response to ETX in absence epilepsy. We conclude that if CACNA1H rare variants predict lack of response to ETX, a larger s le is necessary to test this with sufficient power. Increased GABA-receptor gene rare variant frequency in absence epilepsy patients who fail initial anti-seizure therapy suggests subtle GABA receptor dysfunction may contribute to the underlying pathophysiology.
Rapid diagnosis of SCA36 in a three-generation family using short-read whole genome sequencing data
Publisher: Cold Spring Harbor Laboratory
Date: 25-11-2019
DOI: 10.1101/851675
Abstract: Spinocerebellar ataxias (SCA) are often caused by expansions of short tandem repeats (STRs). Recent methodological advances have made repeat expansion (RE) detection with whole genome sequencing (WGS) feasible. To determine the genetic basis of ataxia in a multigenerational Australian pedigree, with autosomal dominant inheritance. WGS was performed on three affected relatives. The sequence data was screened for known pathogenic REs using two repeat expansion detection tools: exSTRa and ExpansionHunter. This screen provided a clear and rapid diagnosis ( five days from receiving the sequencing data) of SCA36, a rare form of ataxia caused by an intronic GGCCTG RE in NOP56 . the that diagnosis of rare ataxias caused by REs is highly feasible and cost effective with WGS. We propose that WGS be implemented as the frontline, cost effective methodology for molecular testing of in iduals with a clinical diagnosis of ataxia.
Serine and Lipid Metabolism in Macular Disease and Peripheral Neuropathy
Publisher: Massachusetts Medical Society
Date: 10-10-2019
Autosomal dominant congenital spinal muscular atrophy: A true form of spinal muscular atrophy caused by early loss of anterior horn cells
Publisher: Oxford University Press (OUP)
Date: 23-05-2012
DOI: 10.1093/BRAIN/AWS108
Abstract: Autosomal dominant congenital spinal muscular atrophy is characterized by predominantly lower limb weakness and wasting, and congenital or early-onset contractures of the hip, knee and ankle. Mutations in TRPV4, encoding a cation channel, have recently been identified in one large dominant congenital spinal muscular atrophy kindred, but the genetic basis of dominant congenital spinal muscular atrophy in many families remains unknown. It has been hypothesized that differences in the timing and site of anterior horn cell loss in the central nervous system account for the variations in clinical phenotype between different forms of spinal muscular atrophy, but there has been a lack of neuropathological data to support this concept in dominant congenital spinal muscular atrophy. We report clinical, electrophysiology, muscle magnetic resonance imaging and histopathology findings in a four generation family with typical dominant congenital spinal muscular atrophy features, without mutations in TRPV4, and in whom linkage to other known dominant neuropathy and spinal muscular atrophy genes has been excluded. The autopsy findings in the proband, who died at 14 months of age from an unrelated illness, provided a rare opportunity to study the neuropathological basis of dominant congenital spinal muscular atrophy. There was a reduction in anterior horn cell number in the lumbar and, to a lesser degree, the cervical spinal cord, and atrophy of the ventral nerve roots at these levels, in the absence of additional peripheral nerve pathology or abnormalities elsewhere along the neuraxis. Despite the young age of the child at the time of autopsy, there was no pathological evidence of ongoing loss or degeneration of anterior horn cells suggesting that anterior horn cell loss in dominant congenital spinal muscular atrophy occurs in early life, and is largely complete by the end of infancy. These findings confirm that dominant congenital spinal muscular atrophy is a true form of spinal muscular atrophy caused by a loss of anterior horn cells localized to lumbar and cervical regions early in development.
Defining malaria parasite population subdivisions, transmission dynamics and infection origins using SNP barcodes
Publisher: Cold Spring Harbor Laboratory
Date: 04-09-2023
Association of SLC32A1 Missense Variants With Genetic Epilepsy With Febrile Seizures Plus
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-05-2021
DOI: 10.1212/WNL.0000000000011855
Abstract: To identify the causative gene in a large unsolved family with genetic epilepsy with febrile seizures plus (GEFS+), we sequenced the genomes of family members, and then determined the contribution of the identified gene to the pathogenicity of epilepsies by examining sequencing data from 2,772 additional patients. We performed whole genome sequencing of 3 members of a GEFS+ family. Subsequently, whole exome sequencing data from 1,165 patients with epilepsy from the Epi4K dataset and 1,329 Australian patients with epilepsy from the Epi25 dataset were interrogated. Targeted resequencing was performed on 278 patients with febrile seizures or GEFS+ phenotypes. Variants were validated and familial segregation examined by Sanger sequencing. Eight previously unreported missense variants were identified in SLC32A1 , coding for the vesicular inhibitory amino acid cotransporter VGAT. Two variants cosegregated with the phenotype in 2 large GEFS+ families containing 8 and 10 affected in iduals, respectively. Six further variants were identified in smaller families with GEFS+ or idiopathic generalized epilepsy (IGE). Missense variants in SLC32A1 cause GEFS+ and IGE. These variants are predicted to alter γ-aminobutyric acid (GABA) transport into synaptic vesicles, leading to altered neuronal inhibition. Examination of further epilepsy cohorts will determine the full genotype–phenotype spectrum associated with SLC32A1 variants.
CYLD is a causative gene for frontotemporal dementia - amyotrophic lateral sclerosis.
Publisher: Elsevier BV
Date: 07-2020
Mutation of the mitochondrial tyrosyl-tRNA synthetase gene, YARS2, causes myopathy, lactic acidosis, and sideroblastic anemia - MLASA syndrome
Publisher: Elsevier BV
Date: 07-2010
Hemispheric cortical dysplasia secondary to a mosaic somatic mutation in MTOR
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-04-2015
Self-reported impact of developmental stuttering across the lifespan
Publisher: Wiley
Date: 21-03-2022
DOI: 10.1111/DMCN.15211
Abstract: To examine the phenomenology of stuttering across the lifespan in the largest prospective cohort to date. Participants aged 7 years and older with a history of developmental stuttering were recruited. Self‐reported phenotypic data were collected online including stuttering symptomatology, co‐occurring phenotypes, genetic predisposition, factors associated with stuttering severity, and impact on anxiety, education, and employment. A total of 987 participants (852 adults: 590 males, 262 females, mean age 49 years [SD = 17 years 10 months range = 18–93 years] and 135 children: 97 males, 38 females, mean age 11 years 4 months [SD = 3 years range = 7–17 years]) were recruited. Stuttering onset occurred at age 3 to 6 years in 64.0%. Blocking (73.2%) was the most frequent phenotype 75.9% had sought stuttering therapy and 15.5% identified as having recovered. Half (49.9%) reported a family history. There was a significant negative correlation with age for both stuttering frequency and severity in adults. Most were anxious due to stuttering (90.4%) and perceived stuttering as a barrier to education and employment outcomes (80.7%). The frequent persistence of stuttering and the high proportion with a family history suggest that stuttering is a complex trait that does not often resolve, even with therapy. These data provide new insights into the phenotype and prognosis of stuttering, information that is critically needed to encourage the development of more effective speech therapies. Half of the study cohort had a family history of stuttering. While 75.9% of participants had sought stuttering therapy, only 15.5% identified as having recovered. There was a significant negative correlation between age and stuttering frequency and severity in adults.
A new dominantly inherited pure cerebellar ataxia, SCA 30
Publisher: BMJ
Date: 09-12-2009
Abstract: The spinocerebellar ataxias (SCAs) are clinically and genetically heterogeneous. Currently, 27 forms are known, with the causative gene identified in 16. Although the majority of dominant pedigrees worldwide have SCAs 1, 2, 3, 6 or 8, new SCAs continue to be delineated. We describe a new disorder: SCA 30. An Australian family of Anglo-Celtic ethnicity manifested a relatively pure, slowly evolving ataxia. Six affected and four unaffected members were personally examined in a standardised fashion. MRI and nerve conduction studies were performed in two. An autosomal genome-wide linkage study was undertaken, and an in silico analysis of potential candidate genes in the linkage region was performed. The six affected members had a relatively pure, slowly evolving ataxia developing in mid to late life, with only minor pyramidal signs and no evidence of neuropathy. All had hypermetric saccades with normal vestibulo-ocular reflex gain. Only one displayed (slight) gaze-evoked nystagmus. MRI showed cerebellar atrophy with preservation of nodulus/uvula and brainstem. Linkage analysis excluded currently known SCAs and identified a logarithm (base 10) of odds score of 3.0 at chromosome 4q34.3-q35.1, distinct from all previously reported loci. In silico prioritisation identified the gene ODZ3 as the most likely contender. SCA 30 is a previously undescribed cause of (relatively) pure adult-onset autosomal dominant cerebellar ataxia. The responsible gene is yet to be determined, but ODZ3 is a plausible candidate.
Loss-of-function variants in the cardiac Kv11.1 channel as a genetic biomarker for SUDEP
Publisher: Cold Spring Harbor Laboratory
Date: 19-03-2021
DOI: 10.1101/2021.03.19.436102
Abstract: To compare the frequency and impact on channel function of KCNH2 variants in SUDEP patients with epilepsy controls comprising patients older than 50 years, a group with low SUDEP risk, and establish loss-of-function KCNH2 variants as predictive biomarkers of SUDEP risk. We searched for KCNH2 variants with a minor allele frequency of 5%. Functional analysis in Xenopus laevis oocytes was performed for all KCNH2 variants identified. KCNH2 variants were found in 11.1% (10/90) of SUDEP in iduals compared to 6.0% (20/332) of epilepsy controls ( p = 0.11). Loss-of-function KCNH2 variants, defined as causing 20% reduction in maximal litude, were observed in 8.9% (8/90) SUDEP patients compared to 3.3% (11/332) epilepsy controls suggesting about three-fold enrichment (nominal p = 0.04). KCNH2 variants that did not change channel function occurred at a similar frequency in SUDEP (2.2% 2/90) and epilepsy control (2.7% 9/332) cohorts ( p 0.99). Rare KCNH2 variants ( 1% allele frequency) associated with greater loss of function and an ∼11-fold enrichment in the SUDEP cohort (nominal p = 0.03). In silico tools were unable to predict the impact of a variant on function highlighting the need for electrophysiological analysis. These data show that loss-of-function KCNH2 variants are enriched in SUDEP patients and suggest that cardiac mechanisms contribute to SUDEP risk. We propose that genetic screening in combination with functional analysis can identify loss-of-function KCNH2 variants that could act as biomarkers of an in idual’s SUDEP risk.
De Novo Mutations in PPP3CA Cause Severe Neurodevelopmental Disease with Seizures
Publisher: Elsevier BV
Date: 10-2017
An ENU-induced mutation of Cdh23 causes congenital hearing loss, but no vestibular dysfunction, in mice
Publisher: Elsevier BV
Date: 08-2011
Splice-altering variant in COL11A1 as a cause of nonsyndromic hearing loss DFNA37
Publisher: Elsevier BV
Date: 04-2019
The Expected Number of Alleles in a Gene Conversion Model with Mutation
Publisher: Elsevier BV
Date: 12-1999
Segregating Sites in a Gene Conversion Model with Mutation
Publisher: Elsevier BV
Date: 12-1998
Abstract: Formulae for the expectation and variance of the number of segregating and homogeneous sites in a s le of two chromosomes are found. The model includes gene conversion and infinitely-many-alleles mutation in a coalescent framework. The corresponding infinitely-many-sites model limits are also found. The formulae for the expectation are extended to any s le size. Comparisons are drawn between the pure mutation model and the model where gene conversion has been added.
DENND5A-related developmental and epileptic encephalopathy driven by loss of symmetric cell division of apical neural progenitors
Publisher: Cold Spring Harbor Laboratory
Date: 26-08-2022
DOI: 10.1101/2022.08.23.22278845
Abstract: Developmental and epileptic encephalopathies (DEE) are a heterogenous group of epilepsies in which altered brain development can lead to developmental delay and seizures, with the epileptic activity further negatively impacting neurodevelopment 1 . Identifying the underlying cause of DEE is essential for progress towards precision therapy. Here we describe a group of patients with DEE that exhibit a unique cluster of neuroanatomical signatures due to biallelic variants in DENND5A . We demonstrate that DENND5A interacts with MUPP1 and PALS1, components of the Crumbs apical polarity complex, which is required for both neural progenitor cell identity and the ability of these stem cells to ide symmetrically 2 . Induced pluripotent stem cells lacking DENND5A fail to undergo symmetric cell ision during neural induction and have an inherent propensity to differentiate into neurons. Similarly, transgenic DENND5A mice, with phenotypes consistent with the human syndrome, have an increased number of neurons in the proliferative adult subventricular zone. Disruption of symmetric cell ision following loss of DENND5A results from misalignment of the mitotic spindle in apical neural progenitors, an observation also observed in PALS1 null zebrafish embryos 3 . This orients cells away from the proliferative apical domain surrounding the ventricles, biasing daughter cells towards a more fate-committed state, and ultimately halting neurodevelopment. This study provides a mechanism behind DENND5A -related DEE that may also be generalizable to other developmental conditions and provides variant-specific clinical information for physicians and families.
Spatial centrosome proteome of human neural cells uncovers disease-relevant heterogeneity
Publisher: American Association for the Advancement of Science (AAAS)
Date: 17-06-2022
Abstract: The centrosome provides an intracellular anchor for the cytoskeleton, regulating cell ision, cell migration, and cilia formation. We used spatial proteomics to elucidate protein interaction networks at the centrosome of human induced pluripotent stem cell–derived neural stem cells (NSCs) and neurons. Centrosome-associated proteins were largely cell type–specific, with protein hubs involved in RNA dynamics. Analysis of neurodevelopmental disease cohorts identified a significant overrepresentation of NSC centrosome proteins with variants in patients with periventricular heterotopia (PH). Expressing the PH-associated mutant pre-mRNA-processing factor 6 (PRPF6) reproduced the periventricular misplacement in the developing mouse brain, highlighting missplicing of transcripts of a microtubule-associated kinase with centrosomal location as essential for the phenotype. Collectively, cell type–specific centrosome interactomes explain how genetic variants in ubiquitous proteins may convey brain-specific phenotypes.
Ultra-Rare Genetic Variation in the Epilepsies: A Whole-Exome Sequencing Study of 17,606 Individuals
Publisher: Elsevier BV
Date: 08-2019
Cathepsin F mutations cause Type B Kufs disease, an adult-onset neuronal ceroid lipofuscinosis
Publisher: Oxford University Press (OUP)
Date: 07-01-2013
DOI: 10.1093/HMG/DDS558
De novo and inherited private variants in MAP1B in periventricular nodular heterotopia
Publisher: Public Library of Science (PLoS)
Date: 08-05-2018
Mutations in Contactin-1, a Neural Adhesion and Neuromuscular Junction Protein, Cause a Familial Form of Lethal Congenital Myopathy
Publisher: Elsevier BV
Date: 12-2008
Homozygous mutation of STXBP5L explains an autosomal recessive infantile-onset neurodegenerative disorder
Publisher: Oxford University Press (OUP)
Date: 11-12-2014
DOI: 10.1093/HMG/DDU614
Abstract: We report siblings of consanguineous parents with an infantile-onset neurodegenerative disorder manifesting a predominant sensorimotor axonal neuropathy, optic atrophy and cognitive deficit. We used homozygosity mapping to identify an ∼12-Mbp interval identical by descent (IBD) between the affected in iduals on chromosome 3q13.13-21.1 with an LOD score of 2.31. We combined family-based whole-exome and whole-genome sequencing of parents and affected siblings and, after filtering of likely non-pathogenic variants, identified a unique missense variant in syntaxin-binding protein 5-like (STXBP5L c.3127G>A, p.Val1043Ile [CCDS43137.1]) in the IBD interval. Considering other modes of inheritance, we also found compound heterozygous variants in FMNL3 (c.114G>C, p.Phe38Leu and c.1372T>G, p.Ile458Leu [CCDS44874.1]) located on chromosome 12. STXBP5L (or Tomosyn-2) is expressed in the central and peripheral nervous system and is known to inhibit neurotransmitter release through inhibition of the formation of the SNARE complexes between synaptic vesicles and the plasma membrane. FMNL3 is expressed more widely and is a formin family protein that is involved in the regulation of cell morphology and cytoskeletal organization. The STXBP5L p.Val1043Ile variant enhanced inhibition of exocytosis in comparison with wild-type (WT) STXBP5L. Furthermore, WT STXBP5L, but not variant STXBP5L, promoted axonal outgrowth in manipulated mouse primary hippoc al neurons. However, the FMNL3 p.Phe38Leu and p.Ile458Leu variants showed minimal effects in these cells. Collectively, our clinical, genetic and molecular data suggest that the IBD variant in STXBP5L is the likely cause of the disorder.
Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies
Publisher: Springer Science and Business Media LLC
Date: 10-12-2018
DOI: 10.1038/S41467-018-07524-Z
Abstract: The epilepsies affect around 65 million people worldwide and have a substantial missing heritability component. We report a genome-wide mega-analysis involving 15,212 in iduals with epilepsy and 29,677 controls, which reveals 16 genome-wide significant loci, of which 11 are novel. Using various prioritization criteria, we pinpoint the 21 most likely epilepsy genes at these loci, with the majority in genetic generalized epilepsies. These genes have erse biological functions, including coding for ion-channel subunits, transcription factors and a vitamin-B6 metabolism enzyme. Converging evidence shows that the common variants associated with epilepsy play a role in epigenetic regulation of gene expression in the brain. The results show an enrichment for monogenic epilepsy genes as well as known targets of antiepileptic drugs. Using SNP-based heritability analyses we disentangle both the unique and overlapping genetic basis to seven different epilepsy subtypes. Together, these findings provide leads for epilepsy therapies based on underlying pathophysiology.
A SLC39A8 variant causes manganese deficiency, and glycosylation and mitochondrial disorders
Publisher: Wiley
Date: 19-12-2017
DOI: 10.1007/S10545-016-0010-6
Abstract: SLC39A8 variants have recently been reported to cause a type II congenital disorder of glycosylation (CDG) in patients with intellectual disability and cerebellar atrophy. Here we report a novel SLC39A8 variant in siblings with features of Leigh-like mitochondrial disease. Two sisters born to consanguineous Lebanese parents had profound developmental delay, dystonia, seizures and failure to thrive. Brain MRI of both siblings identified bilateral basal ganglia hyperintensities on T2-weighted imaging and cerebral atrophy. CSF lactate was elevated in patient 1 and normal in patient 2. Respiratory chain enzymology was only performed on patient 1 and revealed complex IV and II + III activity was low in liver, with elevated complex I activity. Complex IV activity was borderline low in patient 1 muscle and pyruvate dehydrogenase activity was reduced. Whole genome sequencing identified a homozygous Chr4(GRCh37):g.103236869C>G c.338G>C p.(Cys113Ser) variant in SLC39A8, located in one of eight regions identified by homozygosity mapping. SLC39A8 encodes a manganese and zinc transporter which localises to the cell and mitochondrial membranes. Patient 2 blood and urine manganese levels were undetectably low. Transferrin electrophoresis of patient 2 serum revealed a type II CDG defect. Oral supplementation with galactose and uridine led to improvement of the transferrin isoform pattern within 14 days of treatment initiation. Oral manganese has only recently been added to the treatment. These results suggest SLC39A8 deficiency can cause both a type II CDG and Leigh-like syndrome, possibly via reduced activity of the manganese-dependent enzymes β-galactosyltransferase and mitochondrial manganese superoxide dismutase.
Divergent amino acid and sphingolipid metabolism in patients with inherited neuro-retinal disease
Publisher: Elsevier BV
Date: 06-2023
Infantile-onset myoclonic developmental and epileptic encephalopathy: A new RARS2 phenotype
Publisher: Wiley
Date: 18-11-2022
DOI: 10.1002/EPI4.12553
Abstract: Recessive variants in RARS2 , a nuclear gene encoding a mitochondrial protein, were initially reported in pontocerebellar hypoplasia. Subsequently, a recessive RARS2 early‐infantile ( weeks) developmental and epileptic encephalopathy was described with hypoglycaemia and lactic acidosis. Here, we describe two unrelated patients with a novel RARS2 phenotype and reanalyse the published RARS2 epilepsy phenotypes and variants. Our novel cases had infantile‐onset myoclonic developmental and epileptic encephalopathy, presenting with a progressive movement disorder from 9 months on a background of normal development. Development plateaued and regressed thereafter, with mild to profound impairment. Multiple drug‐resistant generalized and focal seizures occurred with episodes of non‐convulsive status epilepticus. Seizure types included absence, atonic, myoclonic, and focal seizures. Electroencephalograms showed diffuse slowing, multifocal, and generalised spike‐wave activity, activated by sleep. Both patients had compound heterozygous RARS2 variants with likely impact on splicing and transcription. Remarkably, of the now 52 RARS2 variants reported in 54 patients, our reanalysis found that 44 (85%) have been shown to or are predicted to affect splicing or gene expression leading to protein truncation or nonsense‐mediated decay. We expand the RARS2 phenotypic spectrum to include infantile encephalopathy and suggest this gene is enriched for pathogenic variants that disrupt splicing.
A novel splice site mutation inEYA4 causes DFNA10 hearing loss
Publisher: Wiley
Date: 15-07-2007
DOI: 10.1002/AJMG.A.31860
Abstract: Nonsyndromic autosomal dominant sensorineural hearing loss (SNHL) at the DFNA10 locus was described in two families in 2001. Causative mutations that affect the EyaHR domain of the 'Eyes absent 4' (EYA4) protein were identified. We report on the clinical and genetic analyses of an Australian family with nonsyndromic SNHL. Screening of the EYA4 gene showed the novel polypyrimidine tract variation ca. 1,282-12T > A that introduces a new 3' splice acceptor site. This is the first report of a point mutation in EYA4 that is hypothesized to lead to aberrant pre-mRNA splicing and human disease. The DFNA10 family described is only the fourth to be identified. One in idual presented with apparently the same phenotype as other affected members of the family. However, genotyping illustrated that he did not share the DFNA10 disease haplotype. Detailed clinical investigation showed differences in the onset and severity of his hearing loss and thus he is presumed to represent a phenocopy, perhaps resulting from long-term exposure to loud noise.
Natural history of HFE simple heterozygosity for C 282Y and H 63D : A prospective 12‐year study
Publisher: Wiley
Date: 16-03-2015
DOI: 10.1111/JGH.12804
Investigation of chromosome 2q in osteoarthritis of the hand: No significant linkage in a Tasmanian population
Publisher: BMJ
Date: 12-2002
Abstract: Previous studies have suggested a strong genetic component to osteoarthritis (OA), especially that of the hand, and three linkage studies have suggested the existence of susceptibility loci in disparate regions of chromosome 2q. To examine for linkage to 2q in a Tasmanian population of women and men with familial hand OA. Hand OA (distal interphalangeal, carpometacarpal, and Heberden's nodes) was assessed by a combination of hand photographs and radiographs. A non-parametric linkage (NPL) analysis was performed on chromosome 2q of 69 members in 22 families with severe distal interphalangeal joint OA using Genehunter. A quantitative trait linkage analysis of a larger group of 456 members in 68 families was also performed using SOLAR. The maximum non-parametric linkage score was 1.05 (p=0.15) at marker IL1R1, close to the centromere. All components of hand OA scores had significant heritability in this dataset (28%-35%, all p<0.001). Despite this, the quantitative trait analysis (after adjustment for age and, where appropriate, sex) yielded maximum LOD scores of 0.90 for Heberden's nodes (both sexes combined), and 1.19 for carpometacarpal OA score (women only). These results do not provide confirmation of linkage on chromosome 2q in the larger white population with hand OA. They suggest that there are regional variations in the genetic cause of hand OA and that other loci not on 2q may be important in this disease.
Mutations in the first MyTH4 domain of MY015A are a common cause of DFNB3 hearing loss
Publisher: Wiley
Date: 04-2009
DOI: 10.1002/LARY.20116
A novel association between a SNP in CYBRD1 and serum ferritin levels in a cohort study of HFE hereditary haemochromatosis
Publisher: Wiley
Date: 14-09-2009
Cerebrospinal fluid liquid biopsy for detecting somatic mosaicism in brain
Publisher: Oxford University Press (OUP)
Date: 2021
DOI: 10.1093/BRAINCOMMS/FCAA235
Abstract: Brain somatic mutations are an increasingly recognized cause of epilepsy, brain malformations and autism spectrum disorders and may be a hidden cause of other neurodevelopmental and neurodegenerative disorders. At present, brain mosaicism can be detected only in the rare situations of autopsy or brain biopsy. Liquid biopsy using cell-free DNA derived from cerebrospinal fluid has detected somatic mutations in malignant brain tumours. Here, we asked if cerebrospinal fluid liquid biopsy can be used to detect somatic mosaicism in non-malignant brain diseases. First, we reliably quantified cerebrospinal fluid cell-free DNA in 28 patients with focal epilepsy and 28 controls using droplet digital PCR. Then, in three patients we identified somatic mutations in cerebrospinal fluid: in one patient with subcortical band heterotopia the LIS1 p. Lys64* variant at 9.4% frequency in a second patient with focal cortical dysplasia the TSC1 p. Phe581His*6 variant at 7.8% frequency and in a third patient with ganglioglioma the BRAF p. Val600Glu variant at 3.2% frequency. To determine if cerebrospinal fluid cell-free DNA was brain-derived, whole-genome bisulphite sequencing was performed and brain-specific DNA methylation patterns were found to be significantly enriched (P = 0.03). Our proof of principle study shows that cerebrospinal fluid liquid biopsy is valuable in investigating mosaic neurological disorders where brain tissue is unavailable.
Multiple sclerosis risk variants regulate gene expression in innate and adaptive immune cells
Publisher: Life Science Alliance, LLC
Date: 09-06-2020
Abstract: At least 200 single-nucleotide polymorphisms (SNPs) are associated with multiple sclerosis (MS) risk. A key function that could mediate SNP-encoded MS risk is their regulatory effects on gene expression. We performed microarrays using RNA extracted from purified immune cell types from 73 untreated MS cases and 97 healthy controls and then performed Cis expression quantitative trait loci mapping studies using additive linear models. We describe MS risk expression quantitative trait loci associations for 129 distinct genes. By extending these models to include an interaction term between genotype and phenotype, we identify MS risk SNPs with opposing effects on gene expression in cases compared with controls, namely, rs2256814 MYT1 in CD4 cells (q = 0.05) and rs12087340 RF00136 in monocyte cells (q = 0.04). The rs703842 SNP was also associated with a differential effect size on the expression of the METTL21B gene in CD8 cells of MS cases relative to controls (q = 0.03). Our study provides a detailed map of MS risk loci that function by regulating gene expression in cell types relevant to MS.
Coalescence time for two genes from a subdivided population
Publisher: Springer Science and Business Media LLC
Date: 11-2001
Abstract: In this paper a new form of the solution for the Laplace transform and moments of the distribution of the waiting time for two genes to coalescence is presented. The two genes are s led from a sub ided population where migration rates between populations are constant in time. Equal subpopulation size is not assumed. For the special case of an island model with equal migration rates between islands, the Laplace transform of the coalescence time and the first and second moments are found explicitly. The new form of the solutions allows numerical calculation. The connection of how the results relate to a panmictic population when migration rates are large is illustrated using strong-migration-limit theory.
Mutations in SH3PXD2B cause Borrone dermato-cardio-skeletal syndrome
Publisher: Springer Science and Business Media LLC
Date: 09-10-2014
Real time, field-deployable whole genome sequencing of malaria parasites using nanopore technology
Publisher: Cold Spring Harbor Laboratory
Date: 21-12-2020
DOI: 10.1101/2020.12.17.423341
Abstract: Malaria parasite genomes have been generated predominantly using short read sequencing technology which can be slow, requires advanced laboratory training and does not adequately interrogate complex genomic regions that harbour important malaria virulence determinants. The portable Oxford Nanopore Technologies MinION platform generates long reads in real time and may overcome these limitations. We present compelling evidence that Nanopore sequencing delivers valuable additional information for malaria parasites with comparable data fidelity for single nucleotide variant (SNV) calls, compared to standard Illumina whole genome sequencing. We demonstrate this through sequencing of pure Plasmodium falciparum DNA, mock infections and natural isolates. Nanopore has low error rates for haploid SNV genotyping and identifies structural variants (SVs) not detected with short reads. Nanopore genomes are directly comparable to publically available genomes and produce high quality end to end chromosome assemblies. Nanopore sequencing will expedite genomic surveillance of malaria and provide new insights into parasite genome biology.
Mutations in DCC cause isolated agenesis of the corpus callosum with incomplete penetrance
Publisher: Springer Science and Business Media LLC
Date: 27-02-2017
DOI: 10.1038/NG.3794
Clinical spectrum of the pentanucleotide repeat expansion in the RFC1 gene in ataxia syndromes
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2020
DOI: 10.1212/WNL.0000000000010744
Abstract: To determine the clinical significance of an intronic biallelic pentanucleotide repeat expansion in the gene encoding replication factor C subunit 1 ( RFC1 ) in patients with late-onset cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS), in patients with other ataxias, and in healthy controls by comprehensive genetic analyses. In this case-control study, we included 457 in iduals comprising 26 patients with complete or incomplete CANVAS, 70 patients with late-onset cerebellar ataxia, 208 healthy controls, and 153 in iduals from 39 multigenerational families without ataxia to determine repeat stability. All 96 patients were screened for the repeat expansion by duplex PCR. To further characterize the repeat type and lengths, we used fragment length analysis, repeat-primed PCR, Sanger sequencing, and Southern blotting. Expression of RFC1 and the neighboring gene WDR19 were determined by quantitative PCR. Massive biallelic pentanucleotide expansions were found in 15/17 patients with complete CANVAS (88%), in 2/9 patients with incomplete CANVAS (22%), in 4/70 patients with unspecified, late-onset cerebellar ataxia (6%), but not in controls. In patients, the expansion comprised 800–1,000 mostly AAGGG repeats. Nonmassively expanded repeat numbers were in the range of 7–137 repeats and relatively stable during transmission. Expression of RFC1 and WDR19 were unchanged and RFC1 intron retention was not found. A biallelic pentanucleotide repeat expansion is a frequent cause of CANVAS and found in a considerable number of patients with an incomplete clinical presentation or other forms of cerebellar ataxia. The mechanism by which the repeat expansions are causing disease remains unclear and warrants further investigations.
Genome-wide analyses identify common variants associated with macular telangiectasia type 2
Publisher: Springer Science and Business Media LLC
Date: 27-02-2017
DOI: 10.1038/NG.3799
Abstract: Idiopathic juxtafoveal retinal telangiectasis type 2 (macular telangiectasia type 2 MacTel) is a rare neurovascular degenerative retinal disease. To identify genetic susceptibility loci for MacTel, we performed a genome-wide association study (GWAS) with 476 cases and 1,733 controls of European ancestry. Genome-wide significant associations (P < 5 × 10
The retinal RNA editome is concentrated in photoreceptor-specific genes and genetically linked to vision loss
Publisher: Cold Spring Harbor Laboratory
Date: 24-06-2023
DOI: 10.1101/2023.06.22.543349
Abstract: Conversion of adenosine in RNA to inosine by ADAR enzymes, termed ‘RNA editing’, occurs at thousands of sites across the transcriptome, and is required for healthy development of the central nervous system. RNA editing can modify protein sequences, and d en the innate immune response. RNA editing is tissue-specific and partly genetically determined. Modifications of RNA editing sites contribute to multiple diseases, particularly neurodevelopmental and neuropsychiatric diseases. Despite the importance of RNA editing in the brain, nothing is known about this process in the human retina. We describe the landscape of retinal editing revealing its importance in key biological processes that underpin vision. We analysed the transcriptomes of donor retinae and identified ∼153,000 high-confidence RNA editing sites. Some 80% of editing sites occurred within protein-coding RNA, with the majority in intronic Alu repeats, and 3’ UTR sequence. Novel retina-specific sites were concentrated in genes related to photoreceptor function and which cause retinitis pigmentosa, most notably in PDE6A. Exonic, protein recoding sites were enriched in zinc-finger domains. AMD subjects exhibit relatively few differences in RNA editing compared to controls, consistent with limited gene expression differences. We identified ∼10,000 editing QTLs. The genetic architecture of editing in the retina resembles the brain, whereas editing and expression QTLs in the retina show modest genetic overlap. We report colocalization between edQTLs and retinal disease GWAS peaks for age-related macular degeneration, glaucoma and macular telangiectasia. These findings provide new insights into epi-transcriptomic regulation of genes critical for vision, and elaborate putative genetic disease driver mechanisms that appear to be independent of changes in gene expression.
Bioinformatics-Based Identification of Expanded Repeats: A Non-reference Intronic Pentamer Expansion in RFC1 Causes CANVAS
Publisher: Elsevier BV
Date: 07-2019
ExpansionHunter Denovo: A computational method for locating known and novel repeat expansions in short-read sequencing data
Publisher: Springer Science and Business Media LLC
Date: 28-04-2020
DOI: 10.1186/S13059-020-02017-Z
Abstract: Repeat expansions are responsible for over 40 monogenic disorders, and undoubtedly more pathogenic repeat expansions remain to be discovered. Existing methods for detecting repeat expansions in short-read sequencing data require predefined repeat catalogs. Recent discoveries emphasize the need for methods that do not require pre-specified candidate repeats. To address this need, we introduce ExpansionHunter Denovo, an efficient catalog-free method for genome-wide repeat expansion detection. Analysis of real and simulated data shows that our method can identify large expansions of 41 out of 44 pathogenic repeats, including nine recently reported non-reference repeat expansions not discoverable via existing methods.
Dominantly inherited ataxia and dysphonia with dentate calcification: spinocerebellar ataxia type 20
Publisher: Oxford University Press (OUP)
Date: 26-02-2004
DOI: 10.1093/BRAIN/AWH139
Molecular characterization of a novel X-linked syndrome involving developmental delay and deafness
Publisher: Wiley
Date: 12-10-2007
DOI: 10.1002/AJMG.A.31995
Abstract: X-linked syndromes associated with developmental delay and sensorineural hearing loss (SNHL) have been characterized at the molecular level, including Mohr-Tranebjaerg syndrome and Norrie disease. In this study we report on a novel X-linked recessive, congenital syndrome in a family with developmental delay and SNHL that maps to a locus associated with mental retardation (MR) for which no causative gene has been identified. The X-linked recessive inheritance and congenital nature of the syndrome was confirmed by detailed clinical investigation and the family history. Linkage mapping of the X-chromosome was conducted to ascertain the disease locus and candidate genes were screened by direct sequencing and STRP analysis. The recessive syndrome was mapped to Xp11.3-q21.32 and a deletion was identified in a regulatory region upstream of the POU3F4 gene in affected family members. Since mutations in POU3F4 cause deafness at the DFN3 locus, the deletion is the likely cause of the SNHL in this family. The choroideremia (CHM) gene was also screened and a novel missense change was identified. The alteration changes the serine residue at position 89 in the Rab escort 1 protein (REP-1) to a cysteine (S89C). Prenylation of Rab proteins was investigated in patients and the location of REP-1 expression in the brain determined. However, subsequent analysis revealed that this change in CHM was polymorphic having no effect on REP-1 function. Although the causative gene at the MR locus in this family has not been identified, there are a number of genes involved in syndromic and nonsyndromic forms of MR that are potential candidates.
Use of copy number deletion polymorphisms to assess DNA chimerism
Publisher: Oxford University Press (OUP)
Date: 08-2014
DOI: 10.1373/CLINCHEM.2013.216077
Abstract: We describe a novel approach that harnesses the ubiquity of copy number deletion polymorphisms in human genomes to definitively detect and quantify chimeric DNA in clinical s les. Unlike other molecular approaches to chimerism analysis, the copy number deletion (CND) method targets genomic loci (& base pairs in length) that are wholly absent from wild-type (i.e., self) background DNA sequences in a sex-independent manner. Bespoke quantitative PCR (qPCR) CND assays were developed and validated using a series of DNA standards and chimeric plasma DNA s les collected from 2 allogeneic kidney transplant recipients and 12 pregnant women. Assay performance and informativeness were assessed using appropriate statistical methods. The CND qPCR assays showed high sensitivity, precision, and reliability for linear quantification of DNA chimerism down to 16 genomic equivalents (i.e., 106 pg). Fetal fraction (%) in 12 singleton male pregnancies was calculated using the CND qPCR approach, which showed closer agreement with single-nucleotide polymorphism–based massively parallel sequencing than the SRY (sex determining region Y) (Y chromosome) qPCR assay. The latter consistently underestimated the fetal fraction relative to the other methods. We also were able to measure biological changes in plasma nonself DNA concentrations in 2 renal transplant recipients. The CND qPCR technique is suitable for measurement of chimerism for monitoring of rejection in allogeneic organ transplantation and quantification of the cell-free fetal DNA fraction in maternal plasma s les used for noninvasive prenatal genetic testing.
Identity-by-Descent Mapping to Detect Rare Variants Conferring Susceptibility to Multiple Sclerosis
Publisher: Public Library of Science (PLoS)
Date: 05-03-2013
Neonatal BCG vaccination is associated with a long-term DNA methylation signature in circulating monocytes
Publisher: American Association for the Advancement of Science (AAAS)
Date: 05-08-2022
Abstract: Trained immunity describes the capacity of innate immune cells to develop heterologous memory in response to certain exogenous exposures. This phenomenon mediates, at least in part, the beneficial off-target effects of the BCG vaccine. Using an in vitro model of trained immunity, we show that BCG exposure induces a persistent change in active histone modifications, DNA methylation, transcription, and adenosine-to-inosine RNA modification in human monocytes. By profiling DNA methylation of circulating monocytes from infants in the MIS BAIR clinical trial, we identify a BCG-associated DNA methylation signature that persisted more than 12 months after neonatal BCG vaccination. Genes associated with this epigenetic signature are involved in viral response pathways, consistent with the reported off-target protection against viral infections in neonates, adults, and the elderly. Our findings indicate that the off-target effects of BCG in infants are accompanied by epigenetic remodeling of circulating monocytes that lasts more than 1 year.
Ultrafast, alignment-free detection of repeat expansions in NGS and RNAseq data
Publisher: Cold Spring Harbor Laboratory
Date: 02-01-2021
DOI: 10.1101/2021.04.05.438449
Abstract: Short tandem repeat expansions are an established cause of diseases such as Huntington’s disease. Bioinformatic methods for detecting repeat expansions in short-read sequencing have revealed new repeat expansions in humans. Current bioinformatic methods to detect repeat expansions require alignment information to identify repetitive motif enrichment at genomic locations. We present superSTR, an ultrafast method that does not require alignment. We demonstrate superSTR’s ability to efficiently process both whole-genome and whole-exome sequencing data. Using superSTR we perform the first analysis of the UK Biobank to efficiently screen the exomes of 49,953 biobank participants for repeat expansions. We identify known mutations, as well as diseases not previously associated with REs. We further demonstrate the first bioinformatic screening of RNA sequencing data to detect repeat expansions in patients with spinocerebellar ataxia and Fuchs’ endothelial corneal dystrophy, and mouse models of myotonic dystrophy. superSTR is a highly computationally-efficient repeat expansion tool screening and detection tool for genomewide novel repeat expansion analysis, significantly outperforming existing methods. superSTR is available from ahlolab/superSTR .
Reanalysis and optimisation of bioinformatic pipelines is critical for mutation detection
Publisher: Hindawi Limited
Date: 31-01-2019
DOI: 10.1002/HUMU.23699
Genetics of reticular pseudodrusen in age-related macular degeneration
Publisher: Elsevier BV
Date: 04-2022
DOI: 10.1016/J.TIG.2022.01.003
Abstract: Reticular pseudodrusen (RPD) are subretinal deposits that, when observed with age-related macular degeneration (AMD), form a distinct phenotype, often associated with late-stage disease. To date, RPD genetic risk associations overlap six well-established AMD-risk regions. Determining RPD-specific underlying genetic causes by using adequate imaging methods should improve our understanding of the pathophysiology of RPD.
Functional analysis of a hypomorphic allele shows that MMP14 catalytic activity is the prime determinant of the Winchester syndrome phenotype
Publisher: Cold Spring Harbor Laboratory
Date: 14-03-2018
DOI: 10.1101/281485
Abstract: Winchester syndrome (WS, MIM #277950) is an extremely rare autosomal recessive skeletal dysplasia characterized by progressive joint destruction and osteolysis. To date, only one missense mutation in MMP14 , encoding the membrane-bound matrix metalloprotease 14, has been reported in WS patients. Here, we report a novel hypomorphic MMP14 p.Arg111His (R111H) allele, associated with a mitigated form of WS. Functional analysis demonstrated that this mutation, in contrast to previously reported human and murine MMP14 mutations, does not affect MMP14’s transport to the cell membrane. Instead, it partially impairs MMP14’s proteolytic activity. This residual activity likely accounts for the mitigated phenotype observed in our patients. Based on our observations as well as previously published data, we hypothesize that MMP14’s catalytic activity is the prime determinant of disease severity. Given the limitations of our in vitro assays in addressing the consequences of MMP14 dysfunction, we generated a novel mmp14a/b knockout zebrafish model. The fish accurately reflected key aspects of the WS phenotype including craniofacial malformations, kyphosis, short-stature and reduced bone density due to defective collagen remodeling. Notably, the zebrafish model will be a valuable tool for developing novel therapeutic approaches to a devastating bone disorder.
Proteomic and metabolomic analyses of mitochondrial complex I-deficient mouse model generated by spontaneous B2 short interspersed nuclear element (SINE) insertion into NADH dehydrogenase (ubiquinone) Fe-S protein 4 (Ndufs4) gene
Publisher: Elsevier BV
Date: 06-2012
Transcriptome analysis of a ring chromosome 20 patient cohort
Publisher: Wiley
Date: 18-11-2021
DOI: 10.1111/EPI.16766
Inference from gene trees in a subdivided population
Publisher: Elsevier BV
Date: 03-2000
Multi-omic analysis of developing human retina and organoids reveals cell-specific cis-regulatory elements and mechanisms of non-coding genetic disease risk
Publisher: Cold Spring Harbor Laboratory
Date: 02-08-2021
DOI: 10.1101/2021.07.31.454254
Abstract: Cis-regulatory elements (CREs) play a critical role in the development, maintenance, and disease-states of all human cell types. In the human retina, CREs have been implicated in a variety of inherited retinal disorders. To characterize cell-class-specific CREs in the human retina and elucidate their potential functions in development and disease, we performed single-nucleus (sn)ATAC-seq and snRNA-seq on the developing and adult human retina and on human retinal organoids. These analyses allowed us to identify cell-class-specific CREs, enriched transcription factor binding motifs, putative target genes, and to examine how these features change over development. By comparing DNA accessibility between the human retina and retinal organoids we found that CREs in organoids are highly correlated at the single-cell level, validating the use of organoids as a model for studying disease-associated CREs. As a proof of concept, we studied the function of a disease-associated CRE at 5q14.3 in organoids, identifying its principal target gene as the miR-9-2 primary transcript and demonstrating a dual role for this CRE in regulating neurogenesis and gene regulatory programs in mature glia. This study provides a rich resource for characterizing cell-class-specific CREs in the human retina and showcases retinal organoids as a model in which to study the function of retinal CREs that influence retinal development and disease. Single-cell map of cis-regulatory elements in developing and adult human retina. Correlation of single-cell DNA accessibility between human retina and retinal organoids. Association of disease risk loci with cell-class-specific accessibility. Modeling of enhancer function at the 5q14.3 retinal disease-risk locus.
Structurally conserved erythrocyte-binding domain in Plasmodium provides a versatile scaffold for alternate receptor engagement
Publisher: Proceedings of the National Academy of Sciences
Date: 29-12-2016
Abstract: Plasmodium vivax is responsible for the most widely distributed recurring human malaria infections whereas Plasmodium falciparum inflicts the most mortality and morbidity in human populations. Malaria parasites enter our blood cells by making proteins that recognize and bind to their cognate receptors on the red blood cell surface. Our research describes, to our knowledge, the first crystal structure of PvRBP2a, an erythrocyte-binding protein from P. vivax, which revealed a structural scaffold similar to that of PfRh5, the essential erythrocyte-binding protein in P. falciparum . Structural comparisons between PvRBP2a and PfRh5 provide an important foundation toward understanding how P. vivax and P. falciparum parasites use a homologous erythrocyte-binding protein family to engage alternate erythrocyte receptors and ultimately govern host cell specificity.
Mutations in LOXHD1, an Evolutionarily Conserved Stereociliary Protein, Disrupt Hair Cell Function in Mice and Cause Progressive Hearing Loss in Humans
Publisher: Elsevier BV
Date: 09-2009
The clinical utility of exome sequencing and extended bioinformatic analyses in adolescents and adults with a broad range of neurological phenotypes: an Australian perspective
Publisher: Elsevier BV
Date: 2021
Autosomal-Recessive Congenital Cerebellar Ataxia Is Caused by Mutations in Metabotropic Glutamate Receptor 1
Publisher: Elsevier BV
Date: 09-2012
Epilepsy subtype-specific copy number burden observed in a genome-wide study of 17458 subjects
Publisher: Oxford University Press (OUP)
Date: 22-06-2020
Abstract: Cytogenic testing is routinely applied in most neurological centres for severe paediatric epilepsies. However, which characteristics of copy number variants (CNVs) confer most epilepsy risk and which epilepsy subtypes carry the most CNV burden, have not been explored on a genome-wide scale. Here, we present the largest CNV investigation in epilepsy to date with 10 712 European epilepsy cases and 6746 ancestry-matched controls. Patients with genetic generalized epilepsy, lesional focal epilepsy, non-acquired focal epilepsy, and developmental and epileptic encephalopathy were included. All s les were processed with the same technology and analysis pipeline. All investigated epilepsy types, including lesional focal epilepsy patients, showed an increase in CNV burden in at least one tested category compared to controls. However, we observed striking differences in CNV burden across epilepsy types and investigated CNV categories. Genetic generalized epilepsy patients have the highest CNV burden in all categories tested, followed by developmental and epileptic encephalopathy patients. Both epilepsy types also show association for deletions covering genes intolerant for truncating variants. Genome-wide CNV breakpoint association showed not only significant loci for genetic generalized and developmental and epileptic encephalopathy patients but also for lesional focal epilepsy patients. With a 34-fold risk for developing genetic generalized epilepsy, we show for the first time that the established epilepsy-associated 15q13.3 deletion represents the strongest risk CNV for genetic generalized epilepsy across the whole genome. Using the human interactome, we examined the largest connected component of the genes overlapped by CNVs in the four epilepsy types. We observed that genetic generalized epilepsy and non-acquired focal epilepsy formed disease modules. In summary, we show that in all common epilepsy types, 1.5–3% of patients carry epilepsy-associated CNVs. The characteristics of risk CNVs vary tremendously across and within epilepsy types. Thus, we advocate genome-wide genomic testing to identify all disease-associated types of CNVs.
Multipoint Approximations of Identity-by-Descent Probabilities for Accurate Linkage Analysis of Distantly Related Individuals
Publisher: Elsevier BV
Date: 03-2008
SNPs in putative regulatory regions identified by human mouse comparative sequencing and transcription factor binding site data
Publisher: Springer Science and Business Media LLC
Date: 10-2002
Spatial distribution of metabolites in primate retina and its relevance to studies of human metabolic retinal disorders
Publisher: Cold Spring Harbor Laboratory
Date: 14-06-2022
DOI: 10.1101/2022.06.13.496007
Abstract: The primate retina has evolved regional specialisations for specific visual functions. The macula is specialised towards high acuity vision and is an area that contains an increased density of cone photoreceptors and signal processing neurons. Different regions in the retina display unique susceptibility to pathology, with many retinal diseases primarily affecting the macula. To better understand the properties of different retinal areas we conducted an untargeted metabolomics analysis on full thickness punches from three different regions (macula, temporal peri-macula and periphery) of primate retina. Half of all metabolites identified showed differential abundance in at least one comparison between the three regions. The unique metabolic phenotype of different retinal regions is likely due to the differential distribution of different cell types in these regions reflecting the specific metabolic requirements of each cell type. Furthermore, mapping metabolomics results from macula-specific eye diseases onto the region-specific distributions of healthy primate retina revealed differential abundance defining systemic metabolic dysregulations that were region specific, highlighting how our results may help to better understand the pathobiology of retinal diseases with region specificity.
Using familial information for variant filtering in high-throughput sequencing studies
Publisher: Springer Science and Business Media LLC
Date: 17-08-2014
Clonal multi-omics reveals Bcor as a negative regulator of emergency dendritic cell development
Publisher: Elsevier BV
Date: 06-2021
Agm1/Pgm3-Mediated Sugar Nucleotide Synthesis Is Essential for Hematopoiesis and Development
Publisher: Informa UK Limited
Date: 08-2007
DOI: 10.1128/MCB.00802-07
SNP barcodes provide higher resolution than microsatellite markers to measure Plasmodium vivax population genetics
Publisher: Springer Science and Business Media LLC
Date: 20-10-2020
DOI: 10.1186/S12936-020-03440-0
Abstract: Genomic surveillance of malaria parasite populations has the potential to inform control strategies and to monitor the impact of interventions. Barcodes comprising large numbers of single nucleotide polymorphism (SNP) markers are accurate and efficient genotyping tools, however may need to be tailored to specific malaria transmission settings, since ‘universal’ barcodes can lack resolution at the local scale. A SNP barcode was developed that captures the ersity and structure of Plasmodium vivax populations of Papua New Guinea (PNG) for research and surveillance. Using 20 high-quality P. vivax genome sequences from PNG, a total of 178 evenly spaced neutral SNPs were selected for development of an licon sequencing assay combining a series of multiplex PCRs and sequencing on the Illumina MiSeq platform. For initial testing, 20 SNPs were lified in a small number of mono- and polyclonal P. vivax infections. The full barcode was then validated by genotyping and population genetic analyses of 94 P. vivax isolates collected between 2012 and 2014 from four distinct catchment areas on the highly endemic north coast of PNG. Diversity and population structure determined from the SNP barcode data was then benchmarked against that of ten microsatellite markers used in previous population genetics studies. From a total of 28,934,460 reads generated from the MiSeq Illumina run, 87% mapped to the PvSalI reference genome with deep coverage (median = 563, range 56–7586) per locus across genotyped s les. Of 178 SNPs assayed, 146 produced high-quality genotypes (minimum coverage = 56X) in more than 85% of P. vivax isolates. No lification bias was introduced due to either polyclonal infection or whole genome lification (WGA) of s les before genotyping. Compared to the microsatellite panels, the SNP barcode revealed greater variability in genetic ersity between populations and geographical population structure. The SNP barcode also enabled assignment of genotypes according to their geographic origins with a significant association between genetic distance and geographic distance at the sub-provincial level. High-throughput SNP barcoding can be used to map variation of malaria transmission dynamics at sub-national resolution. The low cost per s le and genotyping strategy makes the transfer of this technology to field settings highly feasible.
Intronic ATTTC repeat expansions in STARD7 in familial adult myoclonic epilepsy linked to chromosome 2
Publisher: Springer Science and Business Media LLC
Date: 29-10-2019
DOI: 10.1038/S41467-019-12671-Y
Abstract: Familial Adult Myoclonic Epilepsy (FAME) is characterised by cortical myoclonic tremor usually from the second decade of life and overt myoclonic or generalised tonic-clonic seizures. Four independent loci have been implicated in FAME on chromosomes (chr) 2, 3, 5 and 8. Using whole genome sequencing and repeat primed PCR, we provide evidence that chr2-linked FAME (FAME2) is caused by an expansion of an ATTTC pentamer within the first intron of STARD7 . The ATTTC expansions segregate in 158/158 in iduals typically affected by FAME from 22 pedigrees including 16 previously reported families recruited worldwide. RNA sequencing from patient derived fibroblasts shows no accumulation of the AUUUU or AUUUC repeat sequences and STARD7 gene expression is not affected. These data, in combination with other genes bearing similar mutations that have been implicated in FAME, suggest ATTTC expansions may cause this disorder, irrespective of the genomic locus involved.
Mutation of the nuclear lamin gene LMNB2 in progressive myoclonus epilepsy with early ataxia
Publisher: Oxford University Press (OUP)
Date: 07-05-2015
DOI: 10.1093/HMG/DDV171
KCTD1 and Scalp-Ear-Nipple (‘Finlay–Marks’) syndrome may be associated with myopia and Thin basement membrane nephropathy through an effect on the collagen IV α3 and α4 chains
Publisher: Informa UK Limited
Date: 29-12-2023
Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage
Publisher: Elsevier BV
Date: 06-2012
Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy
Publisher: Springer Science and Business Media LLC
Date: 21-10-2012
DOI: 10.1038/NG.2440
Abstract: We performed genomic mapping of a family with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) and intellectual and psychiatric problems, identifying a disease-associated region on chromosome 9q34.3. Whole-exome sequencing identified a mutation in KCNT1, encoding a sodium-gated potassium channel subunit. KCNT1 mutations were identified in two additional families and a sporadic case with severe ADNFLE and psychiatric features. These findings implicate the sodium-gated potassium channel complex in ADNFLE and, more broadly, in the pathogenesis of focal epilepsies.
Detecting Expansions of Tandem Repeats in Cohorts Sequenced with Short-Read Sequencing Data
Publisher: Elsevier BV
Date: 12-2018
Capturing simple and complex time-dependent effects using flexible parametric survival models: A simulation study
Publisher: Informa UK Limited
Date: 08-07-2021
Recessive variants in ZNF142 cause a complex neurodevelopmental disorder with intellectual disability, speech impairment, seizures, and dystonia
Publisher: Elsevier BV
Date: 11-2019
Ultra-rare genetic variation in the epilepsies: a whole-exome sequencing study of 17,606 individuals
Publisher: Cold Spring Harbor Laboratory
Date: 21-01-2019
DOI: 10.1101/525683
Abstract: Sequencing-based studies have identified novel risk genes for rare, severe epilepsies and revealed a role of rare deleterious variation in common epilepsies. To identify the shared and distinct ultra-rare genetic risk factors for rare and common epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected in iduals and 8,364 controls of European ancestry. We focused on three phenotypic groups the rare but severe developmental and epileptic encephalopathies (DEE), and the commoner phenotypes of genetic generalized epilepsy (GGE) and non-acquired focal epilepsy (NAFE). We observed that compared to controls, in iduals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy, with the strongest enrichment seen in DEE and the least in NAFE. Moreover, we found that inhibitory GABA A receptor genes were enriched for missense variants across all three classes of epilepsy, while no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEE and GGE. Although no single gene surpassed exome-wide significance among in iduals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the top associations, including CACNA1G, EEF1A2 , and GABRG2 for GGE and LGI1, TRIM3 , and GABRG2 for NAFE. Our study confirms a convergence in the genetics of common and rare epilepsies associated with ultra-rare coding variation and highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology in the largest epilepsy WES study to date.
Author Correction: Variants in SART3 cause a spliceosomopathy characterised by failure of testis development and neuronal defects (Nature Communications, (2023), 14, 1, (3403), 10.1038/s41467-023-39040-0)
Publisher: Springer Science and Business Media LLC
Date: 15-06-2023
A family study implicates GBE1 in the etiology of autism spectrum disorder
Publisher: Hindawi Limited
Date: 21-10-2022
DOI: 10.1002/HUMU.24289
Mosaic uniparental disomy results in GM1 gangliosidosis with normal enzyme assay
Publisher: American Medical Association (AMA)
Date: 12-11-2017
Analysis of genome-wide association study data using the protein knowledge base
Publisher: Springer Science and Business Media LLC
Date: 13-11-2011
Abstract: Genome-wide association studies (GWAS) aim to identify causal variants and genes for complex disease by independently testing a large number of SNP markers for disease association. Although genes have been implicated in these studies, few utilise the multiple-hit model of complex disease to identify causal candidates. A major benefit of multi-locus comparison is that it compensates for some shortcomings of current statistical analyses that test the frequency of each SNP in isolation for the phenotype population versus control. Here we developed and benchmarked several protocols for GWAS data analysis using different in-silico gene prediction and prioritisation methodologies. We adopted a high sensitivity approach to the data, using less conservative statistical SNP associations. Multiple gene search spaces, either of fixed-widths or proximity-based, were generated around each SNP marker. We used the candidate disease gene prediction system Gentrepid to identify candidates based on shared biomolecular pathways or domain-based protein homology. Predictions were made either with phenotype-specific known disease genes as input or without a priori knowledge, by exhaustive comparison of genes in distinct loci. Because Gentrepid uses biomolecular data to find interactions and common features between genes in distinct loci of the search spaces, it takes advantage of the multi-locus aspect of the data. Results suggest testing multiple SNP-to-gene search spaces compensates for differences in phenotypes, populations and SNP platforms. Surprisingly, domain-based homology information was more informative when benchmarked against gene candidates reported by GWA studies compared to previously determined disease genes, possibly suggesting a larger contribution of gene homologs to complex diseases than Mendelian diseases.
SIS-seq, a molecular ‘time machine’, connects single cell fate with gene programs
Publisher: Cold Spring Harbor Laboratory
Date: 29-08-2018
DOI: 10.1101/403113
Abstract: Conventional single cell RNA-seq methods are destructive, such that a given cell cannot also then be tested for fate and function, without a time machine. Here, we develop a clonal method SIS-seq , whereby single cells are allowed to ide, and progeny cells are assayed separately in SIS ter conditions some for fate, others by RNA- seq . By cross-correlating progenitor gene expression with mature cell fate within a clone, and doing this for many clones, we can identify the earliest gene expression signatures of dendritic cell subset development. SIS-seq could be used to study other populations harboring clonal heterogeneity, including stem, reprogrammed and cancer cells to reveal the transcriptional origins of fate decisions.
Variants in SART3 cause a spliceosomopathy characterised by failure of testis development and neuronal defects
Publisher: Springer Science and Business Media LLC
Date: 09-06-2023
DOI: 10.1038/S41467-023-39040-0
Abstract: Squamous cell carcinoma antigen recognized by T cells 3 ( SART3 ) is an RNA-binding protein with numerous biological functions including recycling small nuclear RNAs to the spliceosome. Here, we identify recessive variants in SART3 in nine in iduals presenting with intellectual disability, global developmental delay and a subset of brain anomalies, together with gonadal dysgenesis in 46,XY in iduals. Knockdown of the Drosophila orthologue of SART3 reveals a conserved role in testicular and neuronal development. Human induced pluripotent stem cells carrying patient variants in SART3 show disruption to multiple signalling pathways, upregulation of spliceosome components and demonstrate aberrant gonadal and neuronal differentiation in vitro. Collectively, these findings suggest that bi-allelic SART3 variants underlie a spliceosomopathy which we tentatively propose be termed INDYGON syndrome ( I ntellectual disability, N eurodevelopmental defects and D evelopmental delay with 46,X Y GON adal dysgenesis). Our findings will enable additional diagnoses and improved outcomes for in iduals born with this condition.
PRIMA1 mutation: A new cause of nocturnal frontal lobe epilepsy
Publisher: Wiley
Date: 03-07-2015
DOI: 10.1002/ACN3.224
Polymorphisms in the receptor tyrosine kinase MERTK gene are associated with Multiple Sclerosis susceptibility
Publisher: Public Library of Science (PLoS)
Date: 08-02-2011
Challenges of diagnostic exome sequencing in an inbred founder population
Publisher: Wiley
Date: 22-04-2013
DOI: 10.1002/MGG3.7
Cutting edge approaches to detecting brain mosaicism associated with common focal epilepsies: implications for diagnosis and potential therapies
Publisher: Informa UK Limited
Date: 22-09-2021
DOI: 10.1080/14737175.2021.1981288
Abstract: Mosaic variants arising in brain tissue are increasingly being recognized as a hidden cause of focal epilepsy. This knowledge gain has been driven by new, highly sensitive genetic technologies and genome-wide analysis of brain tissue from surgical resection or autopsy in a small proportion of patients with focal epilepsy. Recently reported novel strategies to detect mosaic variants limited to brain have exploited trace brain DNA obtained from cerebrospinal fluid liquid biopsies or stereo-electroencephalography electrodes. The authors review the data on these innovative approaches published in PubMed before 12 June 2021, discuss the challenges associated with their application, and describe how they are likely to improve detection of mosaic variants to provide new molecular diagnoses and therapeutic targets for focal epilepsy, with potential utility in other nonmalignant neurological disorders. These cutting-edge approaches may reveal the hidden genetic etiology of focal epilepsies and provide guidance for precision medicine.
Epidemiology and etiology of infantile developmental and epileptic encephalopathies in Tasmania
Publisher: Wiley
Date: 22-07-2019
DOI: 10.1002/EPI4.12350
Rapid Diagnosis of Spinocerebellar Ataxia 36 in a Three-Generation Family Using Short-Read Whole-Genome Sequencing Data
Publisher: Wiley
Date: 14-05-2020
DOI: 10.1002/MDS.28105
Genetic aetiologies for childhood speech disorder: novel pathways co-expressed during brain development
Publisher: Springer Science and Business Media LLC
Date: 18-09-2023
DOI: 10.1038/S41380-022-01764-8
Abstract: Childhood apraxia of speech (CAS), the prototypic severe childhood speech disorder, is characterized by motor programming and planning deficits. Genetic factors make substantive contributions to CAS aetiology, with a monogenic pathogenic variant identified in a third of cases, implicating around 20 single genes to date. Here we aimed to identify molecular causation in 70 unrelated probands ascertained with CAS. We performed trio genome sequencing. Our bioinformatic analysis examined single nucleotide, indel, copy number, structural and short tandem repeat variants. We prioritised appropriate variants arising de novo or inherited that were expected to be damaging based on in silico predictions. We identified high confidence variants in 18/70 (26%) probands, almost doubling the current number of candidate genes for CAS. Three of the 18 variants affected SETBP1 , SETD1A and DDX3X , thus confirming their roles in CAS, while the remaining 15 occurred in genes not previously associated with this disorder. Fifteen variants arose de novo and three were inherited. We provide further novel insights into the biology of child speech disorder, highlighting the roles of chromatin organization and gene regulation in CAS, and confirm that genes involved in CAS are co-expressed during brain development. Our findings confirm a diagnostic yield comparable to, or even higher, than other neurodevelopmental disorders with substantial de novo variant burden. Data also support the increasingly recognised overlaps between genes conferring risk for a range of neurodevelopmental disorders. Understanding the aetiological basis of CAS is critical to end the diagnostic odyssey and ensure affected in iduals are poised for precision medicine trials.
Deletions in VANGL1 are a risk factor for antibody-mediated kidney disease
Publisher: Elsevier BV
Date: 12-2021
HumanMSD and MouseMSD: generating genetic maps for human and murine microsatellite markers
Publisher: Oxford University Press (OUP)
Date: 24-06-2004
DOI: 10.1093/BIOINFORMATICS/BTH375
Abstract: Summary: We present two Web interfaces that generate genetic maps for given sets of human or mouse microsatellite markers. The genetic maps are generated from available databases using linear interpolation of physical map distances to infer genetic map positions for missing markers in these databases. Availability: bioinf.wehi.edu.au/software/MarkerSearch Supplementary information: bioinf.wehi.edu.au/genetics/index.html (further information about microsatellite markers and linkage mapping). bioinf.wehi.edu.au/software/MarkerSearch/estimateresult.txt (list of chosen markers with percentage errors for the different bins).
A founder mutation in PET100 causes isolated complex IV deficiency in lebanese individuals with Leigh syndrome
Publisher: Elsevier BV
Date: 02-2014
Epidemiology and etiology of infantile developmental and epileptic encephalopathies in Tasmania
Publisher: Oxford University Press (OUP)
Date: 19-06-2019
DOI: 10.1093/BRAIN/AWS151
Abstract: Dravet syndrome is a severe infantile onset epileptic encephalopathy associated with mutations in the sodium channel alpha 1 subunit gene SCN1A. To date no large studies have systematically examined the prognostic, clinical and demographic features of the disease. We prospectively collected data on a UK cohort of in iduals with Dravet syndrome during a 5-year study period and analysed demographic information based on UK population and birth figures. From structured referral data we examined a range of clinical characteristics including epilepsy phenotype, seizure precipitants, electroencephalography data, imaging studies, mutation class and response to medication. Predictors of developmental outcome were determined by logistic regression. We identified 241 cases with SCN1A mutation-positive Dravet syndrome, 207 of which were UK-based. The incidence of mutation-positive Dravet syndrome is at least 1:40 900 UK births. Clinical features predicting a worse developmental outcome included status epilepticus (odds ratio = 3.1 confidence interval = 1.5-6.3 P = 0.003), interictal electroencephalography abnormalities in the first year of life (odds ratio = 5.7 confidence interval = 1.9-16.8 P = 0.002) and motor disorder (odds ratio = 3.3 confidence interval = 1.7-6.4 P < 0.001). No significant effect was seen for seizure precipitants, magnetic resonance imaging abnormalities or mutation class (truncating versus missense). Abnormal magnetic resonance imaging was documented in 11% of cases, principally with findings of non-specific brain atrophy or hippoc al changes. Sodium valproate, benzodiazepines and topiramate were reported as being the most helpful medications at the time of referral. Aggravation of seizures was reported for carbamazepine and lamotrigine. The identification of factors influencing prognosis both aids counselling and encourages early, syndrome-specific therapy. Prevention of status epilepticus with regular medication and emergency protocols is important and may influence developmental outcome.
Dating rare mutations from small samples with dense marker data
Publisher: Oxford University Press (OUP)
Date: 08-2014
DOI: 10.1534/GENETICS.114.164616
Abstract: We present a method for estimating the age of a mutation based on the genetic length of ancestral haplotypes shared between in iduals carrying the mutation. The method can be reliably applied to small s les, typical of situations involving rare mutations, and makes effective use of modern high-density SNP data, thus overcoming two of the limitations with existing methods. The method provides age estimates and confidence intervals without the use of asymptotic theory and is applicable to genealogies in which the data are independent or correlated. In the correlated case we estimate the correlation directly from the data, rather than relying on a model for the genealogy. To demonstrate the method’s efficacy, we provide simulation results and compare it to other methods. The length data are obtained with a simple procedure, and an R script is available for performing the calculations.
Evidence for a Dual-Pathway, 2-Hit Genetic Model for Focal Cortical Dysplasia and Epilepsy
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 25-01-2022
DOI: 10.1212/NXG.0000000000000652
Abstract: The 2-hit model of genetic disease is well established in cancer, yet has only recently been reported to cause brain malformations associated with epilepsy. Pathogenic germline and somatic variants in genes in the mechanistic target of rapamycin (mTOR) pathway have been implicated in several malformations of cortical development. We investigated the 2-hit model by performing genetic analysis and searching for germline and somatic variants in genes in the mTOR and related pathways. We searched for germline and somatic pathogenic variants in 2 brothers with drug-resistant focal epilepsy and surgically resected focal cortical dysplasia (FCD) type IIA. Exome sequencing was performed on blood- and brain-derived DNA to identify pathogenic variants, which were validated by droplet digital PCR. In vitro functional assays of a somatic variant were performed. Exome analysis revealed a novel, maternally inherited, germline pathogenic truncation variant (c.48delG p.Ser17Alafs*70) in NPRL3 in both brothers. NPRL3 is a known FCD gene that encodes a negative regulator of the mTOR pathway. Somatic variant calling in brain-derived DNA from both brothers revealed a low allele fraction somatic variant (c.338C T p.Ala113Val) in the WNT2 gene in 1 brother, confirmed by droplet digital PCR. In vitro functional studies suggested a loss of WNT2 function as a consequence of this variant. A second somatic variant has not yet been found in the other brother. We identify a pathogenic germline mTOR pathway variant ( NPRL3 ) and a somatic variant ( WNT2 ) in the intersecting WNT signaling pathway, potentially implicating the WNT2 gene in FCD and supporting a dual-pathway 2-hit model. If confirmed in other cases, this would extend the 2-hit model to pathogenic variants in different genes in critical, intersecting pathways in a malformation of cortical development. Detection of low allele fraction somatic second hits is challenging but promises to unravel the molecular architecture of FCDs.
AmpSeqR: an R package for amplicon deep sequencing data analysis
Publisher: F1000 Research Ltd
Date: 23-03-2023
DOI: 10.12688/F1000RESEARCH.129581.1
Abstract: Amplicon sequencing (AmpSeq) is a methodology that targets specific genomic regions of interest for polymerase chain reaction (PCR) lification so that they can be sequenced to a high depth of coverage. Amplicons are typically chosen to be highly polymorphic, usually with several highly informative, high frequency single nucleotide polymorphisms (SNPs) segregating in an licon of 100–200 base pair (bp). This allows high sensitivity detection and quantification of the frequency of each sequence within each s le making it suitable for applications such as low frequency somatic mosaicism detection or minor clone detection in mixed s les. AmpSeq is being increasingly applied to both biological and medical studies, in applications such as cancer, infectious diseases and brain mosaicism studies. Current bioinformatics pipelines for AmpSeq data processing lack downstream analysis, have difficulty distinguishing between true sequences and PCR sequencing errors and artifacts, and often require bioinformatic expertise. We present a new R package: AmpSeqR, designed for the processing of deep short-read licon sequencing data, with a focus on infectious diseases. The pipeline integrates several existing R packages combining them with newly developed functions to perform optimal filtering of reads to remove noise and improve the accuracy of the detected sequences data, permitting detection of very low frequency clones in mixed s les. The package provides useful functions including data pre-processing, licon sequence variants (ASVs) estimation, data post-processing, data visualization, and automatically generates a comprehensive Rmarkdown report that contains all essential results facilitating easy inclusion into reports and publications. AmpSeqR is publicly available at ahlolab/AmpSeqR .
A set of regulatory genes co-expressed in embryonic human brain is implicated in disrupted speech development
Publisher: Springer Science and Business Media LLC
Date: 20-02-2019
PacBio long-read amplicon sequencing enables scalable high-resolution population allele typing of the complex CYP2D6 locus
Publisher: Springer Science and Business Media LLC
Date: 25-02-2022
DOI: 10.1038/S42003-022-03102-8
Abstract: The CYP2D6 enzyme is estimated to metabolize 25% of commonly used pharmaceuticals and is of intense pharmacogenetic interest due to the polymorphic nature of the CYP2D6 gene. Accurate allele typing of CYP2D6 has proved challenging due to frequent copy number variants (CNVs) and paralogous pseudogenes. SNP-arrays, qPCR and short-read sequencing have been employed to interrogate CYP2D6 , however these technologies are unable to capture longer range information. Long-read sequencing using the PacBio Single Molecule Real Time (SMRT) sequencing platform has yielded promising results for CYP2D6 allele typing. However, previous studies have been limited in scale and have employed nascent data processing pipelines. We present a robust data processing pipeline “PLASTER” for accurate allele typing of SMRT sequenced licons. We demonstrate the pipeline by typing CYP2D6 alleles in a large cohort of 377 Solomon Islanders. This pharmacogenetic method will improve drug safety and efficacy through screening prior to drug administration.
Blood pressure QTLs identified by genome-wide linkage analysis and dependence on associated phenotypes
Publisher: American Physiological Society
Date: 28-02-2002
DOI: 10.1152/PHYSIOLGENOMICS.00069.2001
Abstract: Understanding genetic factors that contribute to population-wide variation in blood pressure is likely to benefit prevention and treatment of cardiovascular disease. The aim of the Victorian Family Heart Study is to identify genes for cardiovascular risk in 783 volunteer adult families recruited from the general population. In this preliminary study we sought to identify quantitative trait loci (QTLs) using a genome-wide linkage analysis in 274 adult sibling pairs of average age 24 yr selected without respect to blood pressure. We compared multipoint linkage results for carefully measured systolic (SBP) and diastolic (DBP) pressures before and after statistical adjustment for covariation with sex, oral contraception, age, height, and weight. The average BP was 123/67 (SD: 12/11) mmHg in males ( n = 283) and 114/64 (SD: 10/9) mmHg in females ( n = 265). Nonparametric Z-scores from multipoint GeneHunter II analysis were “suggestive” (3.1 or more) at four QTLs for SBP (chromosomes 1, 4, 16, and X) but at no QTLs for DBP. Most Z-scores were affected little by adjustment for covariates. However, the SBP QTL on chromosome 16 was obvious only for unadjusted pressures. This population-based quantitative trait analysis has identified more QTLs than any of the eight previous genome-wide scans for blood pressure. Considerable discrepancies between different studies may reflect the presence of false-positive results or real biological differences between populations.
Familial Cerebellar Ataxia and Amyotrophic Lateral Sclerosis/Frontotemporal Dementia with DAB1 and C9ORF72 Repeat Expansions: An 18-Year Study
Publisher: Wiley
Date: 23-09-2022
DOI: 10.1002/MDS.29221
Abstract: Coding and noncoding repeat expansions are an important cause of neurodegenerative diseases. This study determined the clinical and genetic features of a large German family that has been followed for almost 2 decades with an autosomal dominantly inherited spinocerebellar ataxia (SCA) and independent co‐occurrence of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We carried out clinical examinations and telephone interviews, reviewed medical records, and performed magnetic resonance imaging and positron emission tomography scans of all available family members. Comprehensive genetic investigations included linkage analysis, short‐read genome sequencing, long‐read sequencing, repeat‐primed polymerase chain reaction, and Southern blotting. The family comprises 118 members across seven generations, 30 of whom were definitely and five possibly affected. In this family, two different pathogenic mutations were found, a heterozygous repeat expansion in C9ORF72 in four patients with ALS/FTD and a heterozygous repeat expansion in DAB1 in at least nine patients with SCA, leading to a diagnosis of DAB1 ‐related ataxia (ATX‐DAB1 SCA37). One patient was affected by ALS and SCA and carried both repeat expansions. The repeat in DAB1 had the same configuration but was larger than those previously described ([ATTTT] ≈75 [ATTTC] ≈40‐100 [ATTTT] ≈415 ). Clinical features in patients with SCA included spinocerebellar symptoms, sometimes accompanied by additional ophthalmoplegia, vertical nystagmus, tremor, sensory deficits, and dystonia. After several decades, some of these patients suffered from cognitive decline and one from additional nonprogressive lower motor neuron affection. We demonstrate genetic and clinical findings during an 18‐year period in a unique family carrying two different pathogenic repeat expansions, providing novel insights into their genotypic and phenotypic spectrums. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Identity-by-descent analyses for measuring population dynamics and selection in recombining pathogens
Publisher: Public Library of Science (PLoS)
Date: 23-05-2018
Loss-of-function variants in Kv11.1 cardiac channels as a biomarker for SUDEP
Publisher: Wiley
Date: 18-05-2021
DOI: 10.1002/ACN3.51381
Abstract: To compare the frequency and impact on the channel function of KCNH2 variants in SUDEP patients with epilepsy controls comprising patients older than 50 years, a group with low SUDEP risk, and establish loss‐of‐function KCNH2 variants as predictive biomarkers of SUDEP risk. We searched for KCNH2 variants with a minor allele frequency of %. Functional analysis in Xenopus laevis oocytes was performed for all KCNH2 variants identified. KCNH2 variants were found in 11.1% (10/90) of SUDEP in iduals compared to 6.0% (20/332) of epilepsy controls ( p = 0.11). Loss‐of‐function KCNH2 variants, defined as causing % reduction in maximal litude, were observed in 8.9% (8/90) SUDEP patients compared to 3.3% (11/332) epilepsy controls suggesting about threefold enrichment (nominal p = 0.04). KCNH2 variants that did not change channel function occurred at a similar frequency in SUDEP (2.2% 2/90) and epilepsy control (2.7% 9/332) cohorts ( p 0.99). Rare KCNH2 variants ( % allele frequency) associated with greater loss of function and an ~11‐fold enrichment in the SUDEP cohort (nominal p = 0.03). In silico tools were unable to predict the impact of a variant on function highlighting the need for electrophysiological analysis. These data show that loss‐of‐function KCNH2 variants are enriched in SUDEP patients when compared to an epilepsy population older than 50 years, suggesting that cardiac mechanisms contribute to SUDEP risk. We propose that genetic screening in combination with functional analysis can identify loss‐of‐function KCNH2 variants that could act as biomarkers of an in idual’s SUDEP risk.
Detection of repeat expansions in large next generation DNA and RNA sequencing data without alignment
Publisher: Springer Science and Business Media LLC
Date: 30-07-2022
DOI: 10.1038/S41598-022-17267-Z
Abstract: Bioinformatic methods for detecting short tandem repeat expansions in short-read sequencing have identified new repeat expansions in humans, but require alignment information to identify repetitive motif enrichment at genomic locations. We present superSTR, an ultrafast method that does not require alignment. superSTR is used to process whole-genome and whole-exome sequencing data, and perform the first STR analysis of the UK Biobank, efficiently screening and identifying known and potential disease-associated STRs in the exomes of 49,953 biobank participants. We demonstrate the first bioinformatic screening of RNA sequencing data to detect repeat expansions in humans and mouse models of ataxia and dystrophy.
Missense mutations in the MLKL ‘brace’ region lead to lethal neonatal inflammation in mice and are present in high frequency in humans
Publisher: Cold Spring Harbor Laboratory
Date: 15-05-2019
DOI: 10.1101/628370
Abstract: We have isolated a mouse strain with a single missense mutation in the gene encoding MLKL, the essential effector of necroptotic cell death. The resulting substitution lies within the two-helix ‘brace’ and confers constitutive, RIPK3 independent, killing activity to MLKL. Mice homozygous for Mlkl D139V develop lethal inflammation within days of birth, implicating the salivary glands and pericardium as hotspots for necroptosis and inflammatory infiltration. The normal development of Mlkl D139V homozygotes until birth, and the absence of any overt phenotype in heterozygotes provides important in vivo precedent for the capacity of cells to clear activated MLKL. These observations offer an important insight into the potential disease-modulating roles of three common human MLKL polymorphisms that encode amino acid substitutions within or adjacent to the brace region. Compound heterozygosity of these variants is found at up to 12-fold the expected frequency in patients that suffer from a pediatric autoinflammatory disease, CRMO.
Expanding the clinical and radiological phenotypes of leukoencephalopathy due to biallelic HMBS mutations
Publisher: Wiley
Date: 04-06-2021
DOI: 10.1002/AJMG.A.62377
Abstract: Pathogenic heterozygous variants in HMBS encoding the enzyme hydroxymethylbilane synthase (HMBS), also known as porphobilinogen deaminase, cause acute intermittent porphyria (AIP). Biallelic variants in HMBS have been reported in a small number of children with severe progressive neurological disease and in three adult siblings with a more slowly, progressive neurological disease and distinct leukoencephalopathy. We report three further adult in iduals who share a distinct pattern of white matter abnormality on brain MRI in association with biallelic variants in HMBS , two in iduals with homozygous variants, and one with compound‐heterozygous variants. We present their clinical and radiological features and compare these with the three adult siblings previously described with leukoencephalopathy and biallelic HMBS variants. All six affected in iduals presented with slowly progressive spasticity, ataxia, peripheral neuropathy, with or without mild cognitive impairment, and/or ocular disease with onset in childhood or adolescence. Their brain MRIs show mainly confluent signal abnormalities in the periventricular and deep white matter and bilateral thalami. This recognizable pattern of MRI abnormalities is seen in all six adults described here. Biallelic variants in HMBS cause a phenotype that is distinct from AIP. It is not known whether AIP treatments benefit in iduals with HMBS ‐related leukoencephalopathy. One in idual reported here had improved neurological function for 12 months following liver transplantation followed by decline and progression of disease.
Systemic lipid dysregulation is a risk factor for macular neurodegenerative disease
Publisher: Springer Science and Business Media LLC
Date: 22-07-2020
DOI: 10.1038/S41598-020-69164-Y
Abstract: Macular Telangiectasia type 2 (MacTel) is an uncommon bilateral retinal disease, in which glial cell and photoreceptor degeneration leads to central vision loss. The causative disease mechanism is largely unknown, and no treatment is currently available. A previous study found variants in genes associated with glycine–serine metabolism ( PSPH , PHGDH and CPS1 ) to be associated with MacTel, and showed low levels of glycine and serine in the serum of MacTel patients. Recently, a causative role of deoxysphingolipids in MacTel disease has been established. However, little is known about possible other metabolic dysregulation. Here we used a global metabolomics platform in a case–control study to comprehensively profile serum from 60 MacTel patients and 58 controls. Analysis of the data, using innovative computational approaches, revealed a detailed, disease-associated metabolic profile with broad changes in multiple metabolic pathways. This included alterations in the levels of several metabolites that are directly or indirectly linked to glycine–serine metabolism, further validating our previous genetic findings. We also found changes unrelated to PSPH, PHGDH and CPS1 activity. Most pronounced, levels of several lipid groups were altered, with increased phosphatidylethanolamines being the most affected lipid group. Assessing correlations between different metabolites across our s les revealed putative functional connections. Correlations between phosphatidylethanolamines and sphingomyelin, and glycine–serine and sphingomyelin, observed in controls, were reduced in MacTel patients, suggesting metabolic re-wiring of sphingomyelin metabolism in MacTel patients. Our findings provide novel insights into metabolic changes associated with MacTel and implicate altered lipid metabolism as a contributor to this retinal neurodegenerative disease.
The Genetics of Epilepsy
Publisher: Annual Reviews
Date: 31-08-2020
DOI: 10.1146/ANNUREV-GENOM-120219-074937
Abstract: Epilepsy encompasses a group of heterogeneous brain diseases that affect more than 50 million people worldwide. Epilepsy may have discernible structural, infectious, metabolic, and immune etiologies however, in most people with epilepsy, no obvious cause is identifiable. Based initially on family studies and later on advances in gene sequencing technologies and computational approaches, as well as the establishment of large collaborative initiatives, we now know that genetics plays a much greater role in epilepsy than was previously appreciated. Here, we review the progress in the field of epilepsy genetics and highlight molecular discoveries in the most important epilepsy groups, including those that have been long considered to have a nongenetic cause. We discuss where the field of epilepsy genetics is moving as it enters a new era in which the genetic architecture of common epilepsies is starting to be unraveled.
A mutation in synaptojanin 2 causes progressive hearing loss in the ENU-mutagenised mouse strain mozart
Publisher: Public Library of Science (PLoS)
Date: 15-03-2011
Cochlear implants for DFNA17 deafness
Publisher: Wiley
Date: 12-2006
IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy
Publisher: Springer Science and Business Media LLC
Date: 13-09-2009
DOI: 10.1038/NG.447
Abstract: Hepatitis C virus (HCV) infects 3% of the world's population. Treatment of chronic HCV consists of a combination of PEGylated interferon-alpha (PEG-IFN-alpha) and ribavirin (RBV). To identify genetic variants associated with HCV treatment response, we conducted a genome-wide association study of sustained virological response (SVR) to PEG-IFN-alpha/RBV combination therapy in 293 Australian in iduals with genotype 1 chronic hepatitis C, with validation in an independent replication cohort consisting of 555 in iduals. We report an association to SVR within the gene region encoding interleukin 28B (IL28B, also called IFNlambda3 rs8099917 combined P = 9.25 x 10(-9), OR = 1.98, 95% CI = 1.57-2.52). IL28B contributes to viral resistance and is known to be upregulated by interferons and by RNA virus infection. These data suggest that host genetics may be useful for the prediction of drug response, and they also support the investigation of the role of IL28B in the treatment of HCV and in other diseases treated with IFN-alpha.
Population-level genome-wide STR typing in Plasmodium species reveals higher resolution population structure and genetic diversity relative to SNP typing
Publisher: Cold Spring Harbor Laboratory
Date: 19-05-2021
DOI: 10.1101/2021.05.19.444768
Abstract: Short tandem repeats (STRs) are highly informative genetic markers that have been used extensively in population genetics analysis. They are an important source of genetic ersity and can also have functional impact. Despite the availability of bioinformatic methods that permit large-scale genome-wide genotyping of STRs from whole genome sequencing data, they have not previously been applied to sequencing data from large collections of malaria parasite field s les. Here, we have genotyped STRs using HipSTR in more than 3,000 Plasmodium falciparum and 174 Plasmodium vivax published whole-genome sequence data from s les collected across the globe. High levels of noise and variability in the resultant callset necessitated the development of a novel method for quality control of STR genotype calls. A set of high-quality STR loci (6,768 from P. falciparum and 3,496 from P. vivax ) were used to study Plasmodium genetic ersity, population structures and genomic signatures of selection and these were compared to genome-wide single nucleotide polymorphism (SNP) genotyping data. In addition, the genome-wide information about genetic variation and other characteristics of STRs in P. falciparum and P. vivax have been made available in an interactive web-based R Shiny application PlasmoSTR ( ahlolab/PlasmoSTR ). Malaria is a severe disease caused by a genus of parasites called Plasmodium and is transmitted to humans through infected Anopheles mosquitoes. P. falciparum and P. vivax are the predominant species responsible for more than 95% of all human malaria infections which continue to pose a significant challenge to human health. Antimalarial drug resistance is a serious threat hindering the elimination of malaria. As such, it is important to understand the role of genomic variation in the development of antimalarial drug resistance. STRs are an important source of genomic variation that, from a population genetics perspective, have several advantages over SNPs, including being highly polymorphic, having a higher mutation rate, and having been widely used to study the population structure and genetic ersity. However, STRs are not routinely genotyped with bioinformatic tools across the whole genome with short read sequencing data because they are difficult to identify and genotype accurately, as they vary in size and may align poorly to the reference genome, therefore requiring rigorous quality control (QC). In this study, we genotype STRs using HipSTR[1] in more than 3,000 P. falciparum and 174 P. vivax whole-genome sequence s les collected world-wide. We develop a multivariable logistic regression model for the measurement and prediction of the quality of STRs. In addition, we use a set of genome-wide high-quality STRs to study parasite population genetics and compare them to genome-wide SNP genotyping data, revealing both high consistency with SNP based signals, as well as identifying some signals unique to the STR marker data. These results demonstrate that the identification of highly informative STR markers from large numbers of population s les is a powerful approach to study the genetic ersity, population structures and genomic signatures of selection in P. falciparum and P. vivax . Furthermore, we built an interactive web-based R Shiny application PlasmoSTR ( ahlolab/PlasmoSTR ) that includes genome-wide information about genetic variation and other characteristics of the high quality STRs identified in P. falciparum and P. vivax , allowing researchers to explore and visualize the specific STRs.
Characterisation of Non-Autoinducing Tropodithietic Acid (TDA) Production from Marine Sponge Pseudovibrio Species
Publisher: MDPI AG
Date: 10-12-2014
DOI: 10.3390/MD12125960
Detecting tandem repeat expansions in cohorts sequenced with short-read sequencing data
Publisher: Cold Spring Harbor Laboratory
Date: 30-06-2017
DOI: 10.1101/157792
Abstract: Repeat expansions cause over 30, predominantly neurogenetic, inherited disorders. These can present with overlapping clinical phenotypes, making molecular diagnosis challenging. Single gene or small panel PCR-based methods are employed to identify the precise genetic cause, but can be slow and costly, and often yield no result. Genomic analysis via whole exome and whole genome sequencing (WES and WGS) is being increasingly performed to diagnose genetic disorders. However, until recently analysis protocols could not identify repeat expansions in these datasets. A new method, called exSTRa ( e xpanded S hort T andem R epeat a lgorithm) for the identification of repeat expansions using either WES or WGS was developed and performance of exSTRa was assessed in a simulation study. In addition, four retrospective cohorts of in iduals with eleven different known repeat expansion disorders were analysed with the new method. Results were assessed by comparing to known disease status. Performance was also compared to three other analysis methods (ExpansionHunter, STRetch and TREDPARSE), which were developed specifically for WGS data. Expansions in the STR loci assessed were successfully identified in WES and WGS datasets by all four methods, with high specificity and sensitivity, excepting the FRAXA STR where expansions were unlikely to be detected. Overall exSTRa demonstrated more robust/superior performance for WES data in comparison to the other three methods. exSTRa can be applied to existing WES or WGS data to identify likely repeat expansions and can be used to investigate any STR of interest, by specifying location and repeat motif. We demonstrate that methods such as exSTRa can be effectively utilized as a screening tool to interrogate WES data generated with PCR-based library preparations and WGS data generated using either PCR-based or PCR-free library protocols, for repeat expansions which can then be followed up with specific diagnostic tests. exSTRa is available via GitHub ( ahlolab/exSTRa ).
Neuropathology of childhood-onset basal ganglia degeneration caused by mutation of VAC14
Publisher: Wiley
Date: 07-11-2017
DOI: 10.1002/ACN3.487
A recombination hotspot leads to sequence variability within a novel gene (AK005651) and contributes to type 1 diabetes susceptibility
Publisher: Cold Spring Harbor Laboratory
Date: 04-11-2010
Abstract: More than 25 loci have been linked to type 1 diabetes (T1D) in the nonobese diabetic (NOD) mouse, but identification of the underlying genes remains challenging. We describe here the positional cloning of a T1D susceptibility locus, Idd11 , located on mouse chromosome 4. Sequence analysis of a series of congenic NOD mouse strains over a critical 6.9-kb interval in these mice and in 25 inbred strains identified several haplotypes, including a unique NOD haplotype, associated with varying levels of T1D susceptibility. Haplotype ersity within this interval between congenic NOD mouse strains was due to a recombination hotspot that generated four crossover breakpoints, including one with a complex conversion tract. The Idd11 haplotype and recombination hotspot are located within a predicted gene of unknown function, which exhibits decreased expression in relevant tissues of NOD mice. Notably, it was the recombination hotspot that aided our mapping of Idd11 and confirms that recombination hotspots can create genetic variation affecting a common polygenic disease. This finding has implications for human genetic association studies, which may be affected by the approximately 33,000 estimated hotspots in the genome.
brain-coX: Investigating and visualising gene co-expression in seven human brain transcriptomic datasets
Publisher: Springer Science and Business Media LLC
Date: 08-06-2017
Spatial distribution of metabolites in the retina and its relevance to studies of metabolic retinal disorders
Publisher: Springer Science and Business Media LLC
Date: 06-02-2023
DOI: 10.1007/S11306-022-01969-6
Abstract: The primate retina has evolved regional specialisations for specific visual functions. The macula is specialised towards high acuity vision and is an area that contains an increased density of cone photoreceptors and signal processing neurons. Different regions in the retina display unique susceptibility to pathology, with many retinal diseases primarily affecting the macula. To better understand the properties of different retinal areas we studied the differential distribution of metabolites across the retina. We conducted an untargeted metabolomics analysis on full-thickness punches from three different regions (macula, temporal peri-macula and periphery) of healthy primate retina. Nearly half of all metabolites identified showed differential abundance in at least one comparison between the three regions. Furthermore, mapping metabolomics results from macula-specific eye diseases onto our region-specific metabolite distributions revealed differential abundance defining systemic metabolic dysregulations that were region specific. The unique metabolic phenotype of different retinal regions is likely due to the differential distribution of different cell types in these regions reflecting the specific metabolic requirements of each cell type. Our results may help to better understand the pathobiology of retinal diseases with region specificity.
Short tandem repeat expansions in sporadic amyotrophic lateral sclerosis and frontotemporal dementia
Publisher: American Association for the Advancement of Science (AAAS)
Date: 05-05-2023
Abstract: Pathogenic short tandem repeat (STR) expansions cause over 20 neurodegenerative diseases. To determine the contribution of STRs in sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), we used ExpansionHunter, REviewer, and polymerase chain reaction validation to assess 21 neurodegenerative disease-associated STRs in whole-genome sequencing data from 608 patients with sporadic ALS, 68 patients with sporadic FTD, and 4703 matched controls. We also propose a data-derived outlier detection method for defining allele thresholds in rare STRs. Excluding C9orf72 repeat expansions, 17.6% of clinically diagnosed ALS and FTD cases had at least one expanded STR allele reported to be pathogenic or intermediate for another neurodegenerative disease. We identified and validated 162 disease-relevant STR expansions in C9orf72 (ALS/FTD), ATXN1 [spinal cerebellar ataxia type 1 (SCA1)], ATXN2 (SCA2), ATXN8 (SCA8), TBP (SCA17), HTT (Huntington’s disease), DMPK [myotonic dystrophy type 1 (DM1)], CNBP (DM2), and FMR1 (fragile-X disorders). Our findings suggest clinical and pathological pleiotropy of neurodegenerative disease genes and highlight their importance in ALS and FTD.
A CCG expansion inABCD3causes oculopharyngodistal myopathy in individuals of European ancestry
Publisher: Cold Spring Harbor Laboratory
Date: 10-10-2023
Familial recurrence risks for multiple sclerosis in Australia
Publisher: BMJ
Date: 07-05-2011
Abstract: Genetic susceptibility to multiple sclerosis (MS) has been recognised for many years. Considerable data exist from the northern hemisphere regarding the familial recurrence risks for MS, but there are few data for the southern hemisphere and regions at lower latitude such as Australia. To investigate the interaction between environmental and genetic causative factors in MS, the authors undertook a familial recurrence risk study in three latitudinally distinct regions of Australia. Immediate and extended family pedigrees have been collected for three cohorts of people with MS in Queensland, Victoria and Tasmania spanning 15° of latitude. Age of onset data from Queensland were utilised to estimate age-adjusted recurrence rates. Recurrence risks in Australia were significantly lower than in studies from northern hemisphere populations. The age-adjusted risk for siblings across Australia was 2.13% compared with 3.5% for the northern hemisphere. A similar pattern was seen for other relatives. The risks to relatives were proportional to the population risks for each site, and hence the sibling recurrence-risk ratio (λ(s)) was similar across all sites. The familial recurrence risk of MS in Australia is lower than in previously reported studies. This is directly related to the lower population prevalence of MS. The overall genetic susceptibility in Australia as measured by the λ(s) is similar to the northern hemisphere, suggesting that the difference in population risk is explained largely by environmental factors rather than by genetic admixture.
Dtangle: Accurate and robust cell type deconvolution
Publisher: Oxford University Press (OUP)
Date: 08-11-2019
DOI: 10.1093/BIOINFORMATICS/BTY926
Abstract: Cell type composition of tissues is important in many biological processes. To help understand cell type composition using gene expression data, methods of estimating (deconvolving) cell type proportions have been developed. Such estimates are often used to adjust for confounding effects of cell type in differential expression analysis (DEA). We propose dtangle, a new cell type deconvolution method. dtangle works on a range of DNA microarray and bulk RNA-seq platforms. It estimates cell type proportions using publicly available, often cross-platform, reference data. We evaluate dtangle on 11 benchmark datasets showing that dtangle is competitive with published deconvolution methods, is robust to outliers and selection of tuning parameters, and is fast. As a case study, we investigate the human immune response to Lyme disease. dtangle’s estimates reveal a temporal trend consistent with previous findings and are important covariates for DEA across disease status. dtangle is on CRAN (ackage=dtangle) or github (dtangle.github.io). Supplementary data are available at Bioinformatics online.
'North Sea' progressive myoclonus epilepsy: Phenotype of subjects with GOSR2 mutation
Publisher: Oxford University Press (OUP)
Date: 28-02-2013
DOI: 10.1093/BRAIN/AWT021
Abstract: We previously identified a homozygous mutation in the Golgi SNAP receptor complex 2 gene (GOSR2) in six patients with progressive myoclonus epilepsy. To define the syndrome better we analysed the clinical and electrophysiological phenotype in 12 patients with GOSR2 mutations, including six new unrelated subjects. Clinical presentation was remarkably similar with early onset ataxia (average 2 years of age), followed by myoclonic seizures at the average age of 6.5 years. Patients developed multiple seizure types, including generalized tonic clonic seizures, absence seizures and drop attacks. All patients developed scoliosis by adolescence, making this an important diagnostic clue. Additional skeletal deformities were present, including pes cavus in four patients and syndactyly in two patients. All patients had elevated serum creatine kinase levels (median 734 IU) in the context of normal muscle biopsies. Electroencephalography revealed pronounced generalized spike and wave discharges with a posterior predominance and photosensitivity in all patients, with focal EEG features seen in seven patients. The disease course showed a relentless decline patients uniformly became wheelchair bound (mean age 13 years) and four had died during their third or early fourth decade. All 12 cases had the same variant (c.430G>T, G144W) and haplotype analyses confirmed a founder effect. The cases all came from countries bounding the North Sea, extending to the coastal region of Northern Norway. 'North Sea' progressive myoclonus epilepsy has a homogeneous clinical presentation and relentless disease course allowing ready identification from the other progressive myoclonus epilepsies.
Insights into malaria susceptibility using genome-wide data on 17,000 individuals from Africa, Asia and Oceania
Publisher: Springer Science and Business Media LLC
Date: 16-12-2019
DOI: 10.1038/S41467-019-13480-Z
Abstract: The human genetic factors that affect resistance to infectious disease are poorly understood. Here we report a genome-wide association study in 17,000 severe malaria cases and population controls from 11 countries, informed by sequencing of family trios and by direct typing of candidate loci in an additional 15,000 s les. We identify five replicable associations with genome-wide levels of evidence including a newly implicated variant on chromosome 6. Jointly, these variants account for around one-tenth of the heritability of severe malaria, which we estimate as ~23% using genome-wide genotypes. We interrogate available functional data and discover an erythroid-specific transcription start site underlying the known association in ATP2B4 , but are unable to identify a likely causal mechanism at the chromosome 6 locus. Previously reported HLA associations do not replicate in these s les. This large dataset will provide a foundation for further research on the genetic determinants of malaria resistance in erse populations.
Generating linkage mapping files from Affymetrix SNP chip data
Publisher: Oxford University Press (OUP)
Date: 12-05-2009
DOI: 10.1093/BIOINFORMATICS/BTP313
Abstract: Summary: LINKDATAGEN is a perl tool that generates linkage mapping input files for five different linkage mapping tools using data from all 11 HAPMAP Phase III populations. It provides rudimentary error checks and is easily amended for personal linkage mapping preferences. Availabilitiy and Implementation: LINKDATAGEN is available from bioinf.wehi.edu.au/software/linkdatagen/ with accompanying annotation files, reference manual and test dataset. Contact: bahlo@wehi.edu.au
A Mouse Model of Harlequin Ichthyosis Delineates a Key Role for Abca12 in Lipid Homeostasis
Publisher: Public Library of Science (PLoS)
Date: 19-09-2008
Related Organisations
Walter And Eliza Hall Institute Of Medical Research
Location: Australia
Related Funding Activities
ARC Future Fellowships - Grant ID: FT100100764
Start Date: 2011
End Date: 12-2014
Amount: $699,512.00
Funder: Australian Research Council
View Funded ActivityLinkage Projects - Grant ID: LP0990067
Start Date: 12-2009
End Date: 12-2012
Amount: $370,000.00
Funder: Australian Research Council
View Funded ActivityLinkage Projects - Grant ID: LP0776744
Start Date: 05-2008
End Date: 03-2011
Amount: $400,000.00
Funder: Australian Research Council
View Funded ActivityDiscovery Projects - Grant ID: DP120100285
Start Date: 03-2012
End Date: 12-2016
Amount: $510,000.00
Funder: Australian Research Council
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