ORCID Profile
0000-0002-4408-2613
Current Organisation
University of South Australia
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Publisher: Springer Science and Business Media LLC
Date: 28-07-2022
Publisher: Wiley
Date: 28-12-2015
DOI: 10.1002/AJMG.A.37527
Abstract: Mutations in COL4A1 are well described and result in brain abnormalities manifesting with severe neurological deficits including cerebral palsy, intellectual disability, and focal epilepsy. Families with mutations in COL4A2 are now emerging with a similar phenotype. We describe a family with an autosomal dominant disorder comprising porencephaly, focal epilepsy, and lens opacities, which was negative for mutations in COL4A1. Using whole exome sequencing of three affected in iduals from three generations, we identified a rare variant in COL4A2. This COL4A2 (c.2399G>A, p.G800E, CCDS41907.1) variant was predicted to be damaging by multiple bioinformatics tools and affects an invariable glycine residue that is essential for the formation of collagen IV heterotrimers. The cataracts identified in this family expand the phenotypic spectrum associated with mutations in COL4A2 and highlight the increasing overlap with phenotypes associated with COL4A1 mutations.
Publisher: Springer Science and Business Media LLC
Date: 10-07-2023
Publisher: Ferrata Storti Foundation (Haematologica)
Date: 08-07-2021
Publisher: Elsevier BV
Date: 2022
DOI: 10.1016/J.GIM.2021.09.001
Abstract: Genetic variants causing aberrant premessenger RNA splicing are increasingly being recognized as causal variants in genetic disorders. In this study, we devise standardized practices for polymerase chain reaction (PCR)-based RNA diagnostics using clinically accessible specimens (blood, fibroblasts, urothelia, biopsy). A total of 74 families with erse monogenic conditions (31% prenatal-congenital onset, 47% early childhood, and 22% teenage-adult onset) were triaged into PCR-based RNA testing, with comparative RNA sequencing for 19 cases. Informative RNA assay data were obtained for 96% of cases, enabling variant reclassification for 75% variants that can be used for genetic counseling (71%), to inform clinical care (32%) and prenatal counseling (41%). Variant-associated mis-splicing was highly reproducible for 28 cases with s les from ≥2 affected in iduals or heterozygotes and 10 cases with ≥2 biospecimens. PCR licons encompassing another segregated heterozygous variant was vital for clinical interpretation of 22 of 79 variants to phase RNA splicing events and discern complete from partial mis-splicing. RNA diagnostics enabled provision of a genetic diagnosis for 64% of recruited cases. PCR-based RNA diagnostics has capacity to analyze 81.3% of clinically significant genes, with long licons providing an advantage over RNA sequencing to phase RNA splicing events. The Australasian Consortium for RNA Diagnostics (SpliceACORD) provide clinically-endorsed, standardized protocols and recommendations for interpreting RNA assay data.
Publisher: Hindawi Limited
Date: 03-05-2021
DOI: 10.1002/HUMU.24207
Abstract: The pioneering discovery research of X-linked intellectual disability (XLID) genes has benefitted thousands of in iduals worldwide however, approximately 30% of XLID families still remain unresolved. We postulated that noncoding variants that affect gene regulation or splicing may account for the lack of a genetic diagnosis in some cases. Detecting pathogenic, gene-regulatory variants with the same sensitivity and specificity as structural and coding variants is a major challenge for Mendelian disorders. Here, we describe three pedigrees with suggestive XLID where distinctive phenotypes associated with known genes guided the identification of three different noncoding variants. We used comprehensive structural, single-nucleotide, and repeat expansion analyses of genome sequencing. RNA-Seq from patient-derived cell lines, reverse-transcription polymerase chain reactions, Western blots, and reporter gene assays were used to confirm the functional effect of three fundamentally different classes of pathogenic noncoding variants: a retrotransposon insertion, a novel intronic splice donor, and a canonical splice variant of an untranslated exon. In one family, we excluded a rare coding variant in ARX, a known XLID gene, in favor of a regulatory noncoding variant in OFD1 that correlated with the clinical phenotype. Our results underscore the value of genomic research on unresolved XLID families to aid novel, pathogenic noncoding variant discovery.
Publisher: American Society of Hematology
Date: 24-03-2020
DOI: 10.1182/BLOODADVANCES.2019000901
Abstract: First reported in 1999, germline runt-related transcription factor 1 (RUNX1) mutations are a well-established cause of familial platelet disorder with predisposition to myeloid malignancy (FPD-MM). We present the clinical phenotypes and genetic mutations detected in 10 novel RUNX1-mutated FPD-MM families. Genomic analyses on these families detected 2 partial gene deletions, 3 novel mutations, and 5 recurrent mutations as the germline RUNX1 alterations leading to FPD-MM. Combining genomic data from the families reported herein with aggregated published data sets resulted in 130 germline RUNX1 families, which allowed us to investigate whether specific germline mutation characteristics (type, location) could explain the large phenotypic heterogeneity between patients with familial platelet disorder and different HMs. Comparing the somatic mutational signatures between the available familial (n = 35) and published sporadic (n = 137) RUNX1-mutated AML patients showed enrichment for somatic mutations affecting the second RUNX1 allele and GATA2. Conversely, we observed a decreased number of somatic mutations affecting NRAS, SRSF2, and DNMT3A and the collective genes associated with CHIP and epigenetic regulation. This is the largest aggregation and analysis of germline RUNX1 mutations performed to date, providing a unique opportunity to examine the factors underlying phenotypic differences and disease progression from FPD to MM.
Publisher: Springer Science and Business Media LLC
Date: 08-06-2023
DOI: 10.1038/S41591-023-02401-9
Abstract: Critically ill infants and children with rare diseases need equitable access to rapid and accurate diagnosis to direct clinical management. Over 2 years, the Acute Care Genomics program provided whole-genome sequencing to 290 families whose critically ill infants and children were admitted to hospitals throughout Australia with suspected genetic conditions. The average time to result was 2.9 d and diagnostic yield was 47%. We performed additional bioinformatic analyses and transcriptome sequencing in all patients who remained undiagnosed. Long-read sequencing and functional assays, ranging from clinically accredited enzyme analysis to bespoke quantitative proteomics, were deployed in selected cases. This resulted in an additional 19 diagnoses and an overall diagnostic yield of 54%. Diagnostic variants ranged from structural chromosomal abnormalities through to an intronic retrotransposon, disrupting splicing. Critical care management changed in 120 diagnosed patients (77%). This included major impacts, such as informing precision treatments, surgical and transplant decisions and palliation, in 94 patients (60%). Our results provide preliminary evidence of the clinical utility of integrating multi-omic approaches into mainstream diagnostic practice to fully realize the potential of rare disease genomic testing in a timely manner.
Publisher: Springer Science and Business Media LLC
Date: 2023
DOI: 10.1038/S41591-022-02142-1
Abstract: Pregnancy loss and perinatal death are devastating events for families. We assessed ‘genomic autopsy’ as an adjunct to standard autopsy for 200 families who had experienced fetal or newborn death, providing a definitive or candidate genetic diagnosis in 105 families. Our cohort provides evidence of severe atypical in utero presentations of known genetic disorders and identifies novel phenotypes and disease genes. Inheritance of 42% of definitive diagnoses were either autosomal recessive (30.8%), X-linked recessive (3.8%) or autosomal dominant (excluding de novos, 7.7%), with risk of recurrence in future pregnancies. We report that at least ten families (5%) used their diagnosis for preimplantation (5) or prenatal diagnosis (5) of 12 pregnancies. We emphasize the clinical importance of genomic investigations of pregnancy loss and perinatal death, with short turnaround times for diagnostic reporting and followed by systematic research follow-up investigations. This approach has the potential to enable accurate counseling for future pregnancies.
Publisher: Oxford University Press (OUP)
Date: 2021
DOI: 10.1093/HMG/DDAB160
Publisher: Hindawi Limited
Date: 29-07-2019
DOI: 10.1002/HUMU.23836
Abstract: The X-linked NLGN3 gene, encoding a postsynaptic cell adhesion molecule, was involved in a nonsyndromic monogenic form of autism spectrum disorder (ASD) by the description of one unique missense variant, p.Arg451Cys (Jamain et al. 2003). We investigated here the pathogenicity of additional missense variants identified in two multiplex families with intellectual disability (ID) and ASD: c.1789C>T, p.Arg597Trp, previously reported by our group (Redin et al. 2014) and present in three affected cousins and c.1540C>T, p.Pro514Ser, identified in two affected brothers. Overexpression experiments in HEK293 and HeLa cell lines revealed that both variants affect the level of the mature NLGN3 protein, its localization at the plasma membrane and its presence as a cleaved form in the extracellular environment, even more drastically than what was reported for the initial p.Arg451Cys mutation. The variants also induced an unfolded protein response, probably due to the retention of immature NLGN3 proteins in the endoplasmic reticulum. In comparison, the c.1894A>G, p.Ala632Thr and c.1022T>C, p.Val341Ala variants, present in males from the general population, have no effect. Our report of two missense variants affecting the normal localization of NLGN3 in a total of five affected in iduals reinforces the involvement of the NLGN3 gene in a neurodevelopmental disorder characterized by ID and ASD.
Publisher: Wiley
Date: 16-05-2022
DOI: 10.5694/MJA2.51517
Publisher: Wiley
Date: 06-03-2020
DOI: 10.1002/AJMG.A.61541
Publisher: Springer Science and Business Media LLC
Date: 27-02-2021
DOI: 10.1186/S12920-021-00911-4
Abstract: Periventricular nodular heterotopia (PNH) is a malformation of cortical development characterized by nodules of abnormally migrated neurons. The cause of posteriorly placed PNH is not well characterised and we present a case that provides insights into the cause of posterior PNH. We report a fetus with extensive posterior PNH in association with biallelic variants in LAMC3 . LAMC3 mutations have previously been shown to cause polymicrogyria and pachygyria in the occipital cortex, but not PNH. The occipital location of PNH in our case and the proposed function of LAMC3 in cortical development suggest that the identified LAMC3 variants may be causal of PNH in this fetus. We hypothesise that this finding extends the cortical phenotype associated with LAMC3 and provides valuable insight into genetic cause of posterior PNH.
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.
No related grants have been discovered for Thi Thuong Ha.