ORCID Profile
0000-0003-4753-7430
Current Organisation
Bond University
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Publisher: Springer Science and Business Media LLC
Date: 29-09-2022
DOI: 10.1007/S12035-022-03039-3
Abstract: Monogenic forms of Alzheimer’s disease (AD) have been identified through mutations in genes such as APP, PSEN1, and PSEN2 , whilst other genetic markers such as the APOE ε carrier allele status have been shown to increase the likelihood of having the disease. Mutations in these genes are not limited to AD, as APP mutations can also cause an amyloid form of cerebral small vessel disease (CSVD) known as cerebral amyloid angiopathy, whilst PSEN1 and PSEN2 are involved in NOTCH3 signalling, a process known to be dysregulated in the monogenic CSVD, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). The overlap between AD genes and causes of CSVD led to the hypothesis that mutations in other genes within the PANTHER AD–presenilin pathway may be novel causes of CSVD in a cohort of clinically suspicious CADASIL patients without a pathogenic NOTCH3 mutation. To investigate this, whole exome sequencing was performed on 50 suspected CADASIL patients with no NOTCH3 mutations, and a targeted gene analysis was completed on the PANTHER. ERN1 was identified as a novel candidate CSVD gene following predicted pathogenic gene mutation analysis. Rare variant burden testing failed to identify an association with any gene however, it did show a nominally significant link with ERN1 and TRPC3. This study provides evidence to support a genetic overlap between CSVD and Alzheimer’s disease.
Publisher: Springer Science and Business Media LLC
Date: 14-06-2022
DOI: 10.1007/S12035-022-02914-3
Abstract: Monogenic forms of cerebral small vessel disease (CSVD) can be caused by both variants in nuclear DNA and mitochondrial DNA (mtDNA). Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is known to have a phenotype similar to Cerebral Autosomal Dominant Arteriopathy with Sub-cortical Infarcts and Leukoencephalopathy (CADASIL), and can be caused by variants in the mitochondrial genome and in several nuclear-encoded mitochondrial protein (NEMP) genes. The aim of this study was to screen for variants in the mitochondrial genome and NEMP genes in a NOTCH3 -negative CADASIL cohort, to identify a potential link between mitochondrial dysfunction and CSVD pathology. Whole exome sequencing was performed for 50 patients with CADASIL-like symptomology on the Ion Torrent system. Mitochondrial sequencing was performed using an in-house designed protocol with sequencing run on the Ion GeneStudio S5 Plus (S5 +). NEMP genes and mitochondrial sequencing data were examined for rare (MAF 0.001), non-synonymous variants that were predicted to have a deleterious effect on the protein. We identified 29 candidate NEMP variants that had links to either MELAS-, encephalopathy-, or Alzheimer’s disease–related phenotypes. Based on these changes, variants affecting POLG , MTO1 , LONP1 , NDUFAF6 , NDUFB3 , and TCIRG1 were thought to play a potential role in CSVD pathology in this cohort. Overall, the exploration of the mitochondrial genome identified a potential role for mitochondrial related proteins and mtDNA variants contributing to CSVD pathologies.
Publisher: Springer Science and Business Media LLC
Date: 08-07-2023
DOI: 10.1007/S00439-023-02584-8
Abstract: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a condition caused by mutations in NOTCH3 and results in a phenotype characterised by recurrent strokes, vascular dementia and migraines. Whilst a genetic basis for the disease is known, the molecular mechanisms underpinning the pathology of CADASIL are still yet to be determined. Studies conducted at the Genomics Research Centre (GRC) have also identified that only 15–23% of in iduals clinically suspected of CADASIL have mutations in NOTCH3. Based on this, whole exome sequencing was used to identify novel genetic variants for CADASIL-like cerebral small-vessel disease (CSVD). Analysis of functionally important variants in 50 in iduals was investigated using overrepresentation tests in Gene ontology software to identify biological processes that are potentially affected in this group of patients. Further investigation of the genes in these processes was completed using the TRAPD software to identify if there is an increased number (burden) of mutations that are associated with CADASIL-like pathology. Results from this study identified that cell–cell adhesion genes were positively overrepresented in the PANTHER GO-slim database. TRAPD burden testing identified n = 15 genes that had a higher number of rare (MAF 0.001) and predicted functionally relevant (SIFT 0.05, PolyPhen 0.8) mutations compared to the gnomAD v2.1.1 exome control dataset. Furthermore, these results identified ARVCF , GPR17 , PTPRS , and CELSR1 as novel candidate genes in CADASIL-related pathology. This study identified a novel process that may be playing a role in the vascular damage related to CADASIL-related CSVD and implicated n = 15 genes in playing a role in the disease.
Publisher: Frontiers Media SA
Date: 07-02-2018
Publisher: Springer Science and Business Media LLC
Date: 08-01-2020
DOI: 10.1186/S40246-019-0255-X
Abstract: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a cerebral small vessel disease caused by mutations in the NOTCH3 gene. Our laboratory has been undertaking genetic diagnostic testing for CADASIL since 1997. Work originally utilised Sanger sequencing methods targeting specific NOTCH3 exons. More recently, next-generation sequencing (NGS)-based technologies such as a targeted gene panel and whole exome sequencing (WES) have been used for improved genetic diagnostic testing. In this study, data from 680 patient s les was analysed for 764 tests utilising 3 different sequencing technologies. Sanger sequencing was performed for 407 tests, a targeted NGS gene panel which includes NOTCH3 exonic regions accounted for 354 tests, and WES with targeted analysis was performed for 3 tests. In total, 14.7% of patient s les ( n = 100/680) were determined to have a mutation. Testing efficacy varied by method, with 10.8% ( n = 44/407) of tests using Sanger sequencing able to identify mutations, with 15.8% ( n = 56/354) of tests performed using the NGS custom panel successfully identifying mutations and a likely non- NOTCH3 pathogenic variant ( n = 1/3) identified through WES. Further analysis was then performed through stratification of the number of mutations detected at our facility based on the number of exons, level of pathogenicity and the classification of mutations as known or novel. A systematic review of NOTCH3 mutation testing data from 1997 to 2017 determined the diagnostic rate of pathogenic findings and found the NGS-customised panel increases our ability to identify disease-causing mutations in NOTCH3 .
Publisher: Springer Science and Business Media LLC
Date: 07-03-2020
Publisher: Elsevier BV
Date: 05-2021
Publisher: Elsevier BV
Date: 11-2019
DOI: 10.1016/J.JMOLDX.2019.07.001
Abstract: In this article, we introduce the variant call format-diagnostic annotation and reporting tool (VCF-DART), a customized analysis pipeline tool for the rapid annotation of variants from exome or genome sequencing and the generation of reports for genetic diagnostics. VCF-DART uses custom gene lists to categorize variants into specific analysis tiers and to subcategorize them on the basis of standard parameters to facilitate the rapid interrogation of potentially pathogenic variants by human operators. The tool uses publicly available databases to identify a range of data to assist with variant classification and curation processes and includes robust logging of parameters and database versions to allow comparison of analyses performed at different times. VCF-DART-an online analysis pipeline for next-generation sequencing data-is a platform agnostic tool that leverages the use of publicly available databases to improve a laboratory's calling ability and reduce analysis times long-term. It also runs highly efficiently and scales from desk and laptop machines to servers. Overall, VCF-DART provides a simple, customizable, and entirely open-source method to identify genetic variants that may be of clinical importance in a variety of genetically important conditions.
Publisher: Springer Science and Business Media LLC
Date: 02-01-2020
DOI: 10.1007/S00438-019-01639-8
Abstract: Adaptation to exercise training is a complex trait that may be influenced by genetic variants. We identified 36 single nucleotide polymorphisms (SNPs) that had been previously associated with endurance or strength performance, exercise-related phenotypes or exercise intolerant disorders. A MassARRAY multiplex genotyping assay was designed to identify associations with these SNPs against collected endurance fitness phenotype parameters obtained from two exercise cohorts (Gene SMART study n = 58 and Hawaiian Ironman Triathlon 2008 n = 115). These parameters included peak power output (PP), a time trial (TT), lactate threshold (LT), maximal oxygen uptake (VO
Start Date: 2019
End Date: 2021
Funder: National Health and Medical Research Council
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