Whole exome sequencing in a large pedigree with DCM identifies a novel mutation in .

TitleWhole exome sequencing in a large pedigree with DCM identifies a novel mutation in .
Publication TypeJournal Article
Year of Publication2020
AuthorsRobyns, T, Willems, R, Van Cleemput, J, Jhangiani, S, Muzny, D, Gibbs, R, Lupski, JR, Breckpot, J, Devriendt, K, Corveleyn, A
JournalActa Cardiol
Date Published2020 Dec

Familial dilated cardiomyopathy (DCM) is genetically heterogeneous and is associated with mutations in at least 40 different genes. Apart from encoding the giant protein Titin, none of these genes have an expected diagnostic yield of more than 5% complicating genetic diagnosis. Whole exome sequencing (WES) is a powerful alternative for the identification of the causal gene, however variant interpretation remains challenging. We report on WES in a large family with autosomal dominant DCM complicated by end stage heart failure and non-sustained ventricular arrhythmias in whom no causative mutation was identified using a targeted gene panel including 28 genes. WES was applied on 2 affected cousins. Stringent filtering of the identified genetic variants was performed including population variant frequencies, in silico analysis, orthologous and paralogous conservation. Subsequently Sanger sequencing was performed for 10 potential disease causing variants 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 arrhythmogenic dilated cardiomyopathy caused by defective splicing of the giant sarcomere protein titin and abnormal calcium handling. We report the identification of a novel mutation in RBM20 by WES in a large pedigree with DCM.

Alternate JournalActa Cardiol
PubMed ID31583969
PubMed Central IDPMC7124986
Grant ListUM1 HG006542 / HG / NHGRI NIH HHS / United States