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Title: Whole Exome Sequencing in a Large Pedigree with DCM Identifies a Novel Mutation in RBM20
Authors: Robyns, Tomas
Van Cleemput, Johan
Willems, Rik
Jhangiani, Shalini
Muzny, Donna
Gibbs, Richard
Lupski, James R
Breckpot, Jeroen
Devriendt, Koenraad
Matthijs, Gert
Corveleyn, Anniek
Issue Date: 10-Nov-2015
Publisher: Lippincott Williams & Wilkins
Host Document: Circulation vol:132 issue:Suppl 3
Conference: AHA Scientific Sessions edition:2015 location:Orlando date:7-11 November 2015
Article number: A11800
Abstract: 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.
Publication status: published
KU Leuven publication type: IMa
Appears in Collections:Cardiology
Laboratory for Genetics of Human Development
Department of Human Genetics - miscellaneous
Laboratory for Molecular Diagnosis

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