Exome Sequencing Identifies a Novel DES Mutation (R227C) in a Chinese Dilated Cardiomyopathy Family

Objectives: Dilated cardiomyopathy (DCM) is a common disease in the clinic, and it is the leading cause of heart failure and sudden cardiac death. Previous studies have proven that genetic factors play a crucial role in the occurrence of DCM; more than 50 disease genes including desmin (DES) have been identified to be associated with DCM. At present, most DES mutations are reported in desmin-related myofibrilla myopathy patients, but variants leading to isolated DCM are rarely reported. Methods: We applied whole-exome sequencing and cardiomyopathy-related gene filtering strategies to discover the genetic factors in a Chinese DCM family. Results: A novel mutation (c.679 C>T /p.R227C) in exon 3 of DES was identified and cosegregated with the affected members of a Chinese family with isolated DCM phenotypes (left ventricle and left atrial diameters). Conclusion: This mutation leads to a substitution of arginine by cysteine and it is predicted to be deleterious by bioinformatics programs. Our study not only contributes to the genetic diagnosis and counseling of families with DCM, but it also further proves that DES mutations may lead to isolated DCM and provides a new case for the study of the relationship between DES mutations and DCM.

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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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Abstract 11800: Whole Exome Sequencing in a Large Pedigree With DCM Identifies a Novel Mutation in RBM20

Circulation ◽

10.1161/circ.132.suppl_3.11800 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Tomas Robyns ◽

Johan Van Cleemput ◽

Rik Willems ◽

Shalini Jhangiani ◽

Donna Muzny ◽

...

Keyword(s):

Dilated Cardiomyopathy ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Scoring System ◽

Diagnostic Yield ◽

Novel Mutation ◽

Genetic Diagnosis ◽

Single Nucleotide Variants ◽

Large Pedigree ◽

Whole Exome

Background and hypothesis: Familial dilated cardiomyopathy (DCM) is genetically heterogeneous and is associated with mutations in at least 30 different genes. None of these genes have an expected diagnostic yield of more than 10% complicating genetic diagnosis. Whole exome sequencing (WES) is a powerful alternative for the identification of the causal gene, however variant interpretation remains challenging. We performed WES in a large family with autosomal dominant DCM complicated by end stage heart failure and ventricular arrhythmias. The index of this family was evaluated previously by means of targeted gene panel analysis including 28 genes, but no causal mutation was found. Methods and results: WES was applied on 2 affected cousins. First, shared heterozygous variants (single nucleotide variants, small insertions and deletions) located inside the exon or at the exon/intron boundary were selected. Synonymous variants were excluded, except if they were located at the exon/intron boundaries. Variants with a minor allele frequency of >0.1% in publically available exome databases (1000 Genomes and ESP) were excluded. Furthermore, variants that were present in an in-house exome cohort performed for other disease entities were also excluded since these probably represent local SNV’s. The remaining 19 variants were evaluated using a comprehensive scoring system that includes different in-silico analysis tools, orthologous and paralogous conservation and population frequencies. Subsequently Sanger sequencing was performed for 10 variants that were classified as likely pathogenic (N=1) or variants of unknown significance (N=9) according to the scoring system in order to confirm the presence of the variant and to evaluate co-segregation. Only one variant in exon 9 of the RBM20 gene (c.2714T>A, p.Met950Lys, NM_001334363) showed full co-segregation in the 7 affected family members resulting in a maximum 2-point LOD score of 2.1 and suggesting this as the pathogenic mutation responsible for the phenotype. Recently mutations in RBM20 have been linked to dilated cardiomyopathy caused by defective splicing of the giant sarcomeric protein titin. Conclusions: We report the identification of a novel mutation in RBM20 by WES in a large pedigree with DCM.

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Whole exome sequencing identifies a novel mutation (c.333 + 2T > C) of TNNI3K in a Chinese family with dilated cardiomyopathy and cardiac conduction disease

Gene ◽

10.1016/j.gene.2018.01.055 ◽

2018 ◽

Vol 648 ◽

pp. 63-67 ◽

Cited By ~ 9

Author(s):

Liang-Liang Fan ◽

Hao Huang ◽

Jie-Yuan Jin ◽

Jing-Jing Li ◽

Ya-Qin Chen ◽

...

Keyword(s):

Dilated Cardiomyopathy ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Novel Mutation ◽

Cardiac Conduction ◽

Chinese Family ◽

Whole Exome

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Identification of Two Novel Mutations in PKHD1 Gene from Two Families with Polycystic Kidney Disease by Whole Exome Sequencing

Current Genomics ◽

10.2174/1389202922666210219111810 ◽

2021 ◽

Vol 22 ◽

Author(s):

Masoud Heidari ◽

Hamid Gharshasbi ◽

Alireza Isazadeh ◽

Morteza Soleyman-Nejad ◽

Mohammad Hossein Taskhiri ◽

...

Keyword(s):

Kidney Disease ◽

Exome Sequencing ◽

Polycystic Kidney Disease ◽

Whole Exome Sequencing ◽

Novel Mutation ◽

Genetic Diagnosis ◽

Genetic Alterations ◽

Polycystic Kidney ◽

Novel Mutations ◽

Whole Exome

Background:: Polycystic kidney disease (PKD) is an autosomal recessive disorder resulting from mutations in the PKHD1 gene on chromosome 6 (6p12), a large gene spanning 470 kb of genomic DNA. Objective: The aim of the present study was to report newly identified mutations in the PKHD1 gene in two Iranian families with PKD. Materials and Methods: Genetic alterations of a 3-month-old boy and a 27-year-old girl with PKD were evaluated using whole-exome sequencing. The PCR direct sequencing was performed to analyse the co-segregation of the variants with the disease in the family. Finally, the molecular function of the identified novel mutations was evaluated by in silico study. Results: In the 3 month-old boy, a novel homozygous frameshift mutation was detected in the PKHD1 gene, which can cause PKD. Moreover, we identified three novel heterozygous missense mutations in ATIC, VPS13B, and TP53RK genes. In the 27-year-old woman, with two recurrent abortions history and two infant mortalities at early weeks due to metabolic and/or renal disease, we detected a novel missense mutation on PKHD1 gene and a novel mutation in ETFDH gene. Conclusion: In general, we have identified two novel mutations in the PKHD1 gene. These molecular findings can help accurately correlate genotype and phenotype in families with such disease in order to reduce patient births through preoperative genetic diagnosis or better management of disorders.

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Screening of Candidate Pathogenic Genes for Spontaneous Abortion using Whole Exome Sequencing

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207324666210628115715 ◽

2021 ◽

Vol 24 ◽

Author(s):

Qingwen Zhu ◽

Yiwen Zhou ◽

Jiayi Ding ◽

Li Chen ◽

Jia Liu ◽

...

Keyword(s):

Exome Sequencing ◽

Whole Exome Sequencing ◽

Spontaneous Abortion ◽

Gene Fusion ◽

High Throughput Sequencing ◽

Kegg Pathway ◽

Novel Mutation ◽

Common Disease ◽

Pathogenic Genes ◽

Whole Exome

Background: Spontaneous abortion is a common disease in obstetrics and reproduction. Objective: This study aimed to screen candidate pathogenic genes for spontaneous abortion using whole-exome sequencing. Methods: Genomic DNA was extracted from abortion tissues of spontaneous abortion patients and sequenced using the Illumina HiSeq2500 high-throughput sequencing platform. Whole exome sequencing was performed to select harmful mutations, including SNP and insertion and deletion sites, associated with spontaneous abortion. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses and gene fusion analyses were performed. MUC3A and PDE4DIP were two novel mutation genes that were screened and verified by PCR in abortion tissues of patients. Results: A total of 83,633 SNPs and 13,635 Indel mutations were detected, of which 29172 SNPs and 3093 Indels were screened as harmful mutations. The 7 GO-BP, 4 GO-CC, 9 GO-MF progress, and 3 KEGG pathways were enriched in GO and KEGG pathway analyses. A total of 746 gene fusion mutations were obtained, involving 492 genes. MUC3A and PDE4DIP were used for PCR verification because of their high number of mutation sites in all samples. Conclusion: There are extensive SNPs and Indel mutations in the genome of spontaneous abortion tissues, and the effect of these gene mutations on spontaneous abortion needs further experimental verification.

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