GW28-e1209 Whole Exome Sequencing Identified a Pathogenic Mutation in RYR2 in a Chinese Family with Unexplained Sudden Death

Dilated cardiomyopathy (DCM) is a severe cardiovascular disease which can lead to heart failure and sudden cardiac death (SCD). The typical feature of DCM is left ventricular enlargement or dilatation. In some conditions, DCM and arrhythmia can occur concurrently, apparently promoting the prevalence of SCD. According to previous studies, mutations in more than 100 genes have been detected in DCM and/or arrhythmia patients. Here, we report a Chinese family with typical DCM, ventricular tachycardia, syncope, and SCD. Using whole-exome sequencing, a novel, likely pathogenic mutation (c.959T>G/p.L320R) of actinin alpha 2 (ACTN2) was identified in all affected family members. This novel mutation was also predicted to be disease-causing by MutationTaster, SIFT, and Polyphen-2. Our study not only expands the spectrum of ACTN2 mutations and contributes to the genetic diagnosis and counseling of the family, but also provides a new case with overlap phenotype that may be caused by the ACTN2 variant.

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A novel TLE6 mutation, c.541+1G>A, identified using whole‐exome sequencing in a Chinese family with female infertility

Molecular Genetics & Genomic Medicine ◽

10.1002/mgg3.1743 ◽

2021 ◽

Author(s):

Bin Mao ◽

Xueling Jia ◽

Hongfang Liu ◽

Xiaojuan Xu ◽

Xiaodong Zhao ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Female Infertility ◽

Chinese Family ◽

Whole Exome

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A Novel Mutation in COL4A1 Gene in a Chinese Family with Pontine Autosomal Dominant Microangiopathy and Leukoencephalopathy

Translational Stroke Research ◽

10.1007/s12975-021-00926-0 ◽

2021 ◽

Author(s):

Qing Li ◽

Chengfeng Wang ◽

Wei Li ◽

Zaiqiang Zhang ◽

Shanshan Wang ◽

...

Keyword(s):

Basement Membrane ◽

Skin Biopsy ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Autosomal Dominant ◽

Chinese Family ◽

Heterozygous Mutation ◽

Collagen Type Iv ◽

Lacunar Infarcts ◽

Whole Exome

AbstractPontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL) is a rare hereditary cerebral small vessel disease. We report a novel collagen type IV alpha 1 (COL4A1) gene mutation in a Chinese family with PADMAL. The index case was followed up for 6 years. Neuroimaging, whole-exome sequencing, skin biopsy, and pedigree analysis were performed. She initially presented with minor head injury at age 38. MRI brain showed chronic lacunar infarcts in the pons, left thalamus, and right centrum semiovale. Extensive workup was unremarkable except for a patent foramen ovale (PFO). Despite anticoagulation, PFO closure, and antiplatelet therapy, the patient had recurrent lacunar infarcts in the pons and deep white matter, as well as subcortical microhemorrhages. Whole-exome sequencing demonstrated a novel c.*34G > T mutation in the 3′ untranslated region of COL4A1 gene. Skin biopsy subsequently demonstrated thickening of vascular basement membrane, proliferation of endothelial cells, and stenosis of vascular lumen. Three additional family members had gene testing and 2 of them were found to have the same heterozygous mutation. Of the 18 individuals in the pedigree of 3 generations, 12 had clinical and MRI evidence of PADMAL. The mechanisms of both ischemic and hemorrhagic stroke are likely the overexpression of COLT4A1 in the basement membrane and frugality of the vessel walls. Our findings suggest that the novel c.*34G > T mutation appears to have the same functional consequences as the previously reported COL4A1 gene mutations in patients with PADMAL and multi-infarct dementia of Swedish type.

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Compound pathogenic mutation in the USH2A gene in Chinese RP families detected by whole‑exome sequencing

Molecular Medicine Reports ◽

10.3892/mmr.2018.9530 ◽

2018 ◽

Cited By ~ 1

Author(s):

Yue‑Chuan Fu ◽

Na Chen ◽

Zi‑Long Qiu ◽

Lin Liu ◽

Jie Shen

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Pathogenic Mutation ◽

Whole Exome

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Whole-Exome Sequencing to Decipher the Genetic Heterogeneity of Hearing Loss in a Chinese Family with Deaf by Deaf Mating

PLoS ONE ◽

10.1371/journal.pone.0109178 ◽

2014 ◽

Vol 9 (10) ◽

pp. e109178 ◽

Cited By ~ 11

Author(s):

Jie Qing ◽

Denise Yan ◽

Yuan Zhou ◽

Qiong Liu ◽

Weijing Wu ◽

...

Keyword(s):

Hearing Loss ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Genetic Heterogeneity ◽

Chinese Family ◽

Whole Exome

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Whole-exome sequencing identify a new mutation of MYH7 in a Chinese family with left ventricular noncompaction

Gene ◽

10.1016/j.gene.2014.12.061 ◽

2015 ◽

Vol 558 (1) ◽

pp. 138-142 ◽

Cited By ~ 9

Author(s):

Jing Yang ◽

Meng Zhu ◽

Yao Wang ◽

Xiaofeng Hou ◽

Hongping Wu ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Left Ventricular ◽

Chinese Family ◽

Left Ventricular Noncompaction ◽

New Mutation ◽

Ventricular Noncompaction ◽

Whole Exome

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Striking Cardiac Phenotypic Variability in A Chinese Family With A MYH7 Splice Site Mutation

10.21203/rs.3.rs-273275/v1 ◽

2021 ◽

Author(s):

Peng Tu ◽

Hairui Sun ◽

Xiaohang Zhang ◽

Qian Ran ◽

suzhen Ran ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Splice Site ◽

Phenotypic Variability ◽

Splice Site Mutation ◽

Left Ventricular ◽

Chinese Family ◽

Site Mutation ◽

Cardiac Phenotype ◽

Whole Exome

Abstract Background: Left ventricular non-compaction cardiomyopathy (LVNC) is a rare congenital heart defect (CHD), genetics defects have been found in patients with LVNC and their family members; and MYH7 is the most common genetic associated with LVNC. Methods: A trio (fetus and the parents) whole-exome sequencing (WES) was performed when the fetus was found with Ebstein's anomaly (EA), heart dilatation, perimembranous ventricular septal defects (VSD), mild seroperitoneum and single umbilical artery (SUA).Results: Whole-exome sequencing identified a maternal inherited heterozygous splice site mutation in MYH7 (NM_000257.3:c.732+1G>A). Subsequent Sanger sequencing confirmed that the mutation was heterozygous in the fetus, the old sister, the grandmother, and the mother. QPCR experiment using RNA from blood lymphocytes but were unable to amplify any product.Conclusion: This familial case underlines that the striking cardiac phenotypic of MYH7 mutation (the c.732+1G>A spice site variant) may be highly variable. The mechanistic studies which could uncover candidate genes modulating cardiac phenotype associated with LVNC/EA should be proceed.

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Re-analysis of whole-exome sequencing data uncovers novel diagnostic variants and improves molecular diagnostic yields for sudden death and idiopathic diseases

Genome Medicine ◽

10.1186/s13073-019-0702-2 ◽

2019 ◽

Vol 11 (1) ◽

Cited By ~ 3

Author(s):

Elias L. Salfati ◽

Emily G. Spencer ◽

Sarah E. Topol ◽

Evan D. Muse ◽

Manuel Rueda ◽

...

Keyword(s):

Sudden Death ◽

Rare Disease ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Diagnostic Yield ◽

Molecular Diagnostic ◽

Sudden Unexplained Death ◽

Unexplained Death ◽

Pathogenic Variants ◽

Whole Exome

Abstract Background Whole-exome sequencing (WES) has become an efficient diagnostic test for patients with likely monogenic conditions such as rare idiopathic diseases or sudden unexplained death. Yet, many cases remain undiagnosed. Here, we report the added diagnostic yield achieved for 101 WES cases re-analyzed 1 to 7 years after initial analysis. Methods Of the 101 WES cases, 51 were rare idiopathic disease cases and 50 were postmortem “molecular autopsy” cases of early sudden unexplained death. Variants considered for reporting were prioritized and classified into three groups: (1) diagnostic variants, pathogenic and likely pathogenic variants in genes known to cause the phenotype of interest; (2) possibly diagnostic variants, possibly pathogenic variants in genes known to cause the phenotype of interest or pathogenic variants in genes possibly causing the phenotype of interest; and (3) variants of uncertain diagnostic significance, potentially deleterious variants in genes possibly causing the phenotype of interest. Results Initial analysis revealed diagnostic variants in 13 rare disease cases (25.4%) and 5 sudden death cases (10%). Re-analysis resulted in the identification of additional diagnostic variants in 3 rare disease cases (5.9%) and 1 sudden unexplained death case (2%), which increased our molecular diagnostic yield to 31.4% and 12%, respectively. Conclusions The basis of new findings ranged from improvement in variant classification tools, updated genetic databases, and updated clinical phenotypes. Our findings highlight the potential for re-analysis to reveal diagnostic variants in cases that remain undiagnosed after initial WES.

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