Whole exome sequencing identifies novel candidate mutations in a Chinese family with left ventricular noncompaction

Introduction: Causal and modifier genes associated with left ventricular noncompaction (LVNC) often occurring in conjunction with other familial cardiomyopathies remain elusive. Hypothesis: The LVNC-associated di- and multigenic abnormalities can be identified by whole exome sequencing (WES). Methods: Five families with a history of LVNC, including five affected probands, three affected family members, and twelve unaffected relatives, were studied. Genomic DNA was extracted from whole blood samples followed by WES and Sanger sequencing to confirm possibly pathogenic variants predicted by in-silico analysis. Phenotype-genotype correlation and quantitative co-segregation studies are performed. Results: We identified nine missense possibly pathogenic variants, a 2-bp frameshift insertion, and a 9-bp in-frame insertion in the five families. Two affected siblings in Family 1 were found carrying digenic heterozygous variants: c.4048G>A (p.E1350K) in MYH7 and c.827C>T (p.A276V) in ANKRD1. Unaffected parents were carriers for each of the two variants. Three affected members, father and two daughters, of Family 2 carried c.550A>C (p.K184Q) variant in MYH7 in contrast to two unaffected members, mother and another daughter. In Family 3, multigenic heterozygosity (c.673G>T (p.D225Y) in CACNA2D1 ; c.440T>A (p.V147E) in COQ4 and c.3700C>A (p.H1234N) in MYH7) was identified in the proband. These variants were found in none of three unaffected relatives. The proband of Family 4 was positive for heterozygous variants: c.2684_2685insAG (p.A897Kfs*3) in DSC2 , c.8633T>C (p.V2878A) in OBSCN , and c.11717C >T (p.T3906I) in PLEC. The T3906I PLEC variant was identified in his unaffected half-sibling and his father, but not in his mother. In Family 5, c. 2591A>T (p.D864V) in HDAC9 , c.9616C>T (p.R3206W) in PLEC and c.954_955insT (p.L319Sfs*74) in MYH14 were identified in the proband. None of those variants were identified in his unaffected sibling. Conclusions: We report several potential pathogenic LVNC-associated variants in novel genes (ANKRD1, DSC2, OBSCN , PLEC, HDAC9, MYH14, COQ4, CACNA2D1) and known genes ( MYH7 and MYH7B). The diverse profile of inheritance (digenic and multigenic heterogeneity) that may cause and modify the heterogeneous LVNC phenotypes.

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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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Whole-Exome Sequencing Identifies a Novel Mutation (p.L320R) of Alpha-Actinin 2 in a Chinese Family with Dilated Cardiomyopathy and Ventricular Tachycardia

Cytogenetic and Genome Research ◽

10.1159/000496077 ◽

2019 ◽

Vol 157 (3) ◽

pp. 148-152 ◽

Cited By ~ 2

Author(s):

Liang-Liang Fan ◽

Hao Huang ◽

Jie-Yuan Jin ◽

Jing-Jing Li ◽

Ya-Qin Chen ◽

...

Keyword(s):

Ventricular Tachycardia ◽

Dilated Cardiomyopathy ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Novel Mutation ◽

Genetic Diagnosis ◽

Pathogenic Mutation ◽

Left Ventricular ◽

Chinese Family ◽

Whole Exome

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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