Reevaluating the Genetic Contribution of Monogenic Dilated Cardiomyopathy

作者：Francesco Mazzarotto, Upasana Tayal, Rachel J. Buchan, William Midwinter, Alicja Wilk, Nicola Whiffin, Risha Govind, Erica Mazaika, Antonio de Marvao, Timothy J. W. Dawes, Leanne E. Felkin, Mian Ahmad, Pantazis I. Theotokis, Elizabeth W. Edwards, Alexander Y. Ing, Kate L. Thomson, Laura Chan, David Sim, Arun John Baksi, Antonis A. Pantazis, Angharad M. Roberts, Hugh C Watkins, Birgit Funke, Declan P. O’Regan, Iacopo Olivotto, Paul J.R. Barton, Sanjay Kumar Prasad, Stuart A. Cook, James S. Ware, Roddy Walsh · 发表于：Circulation · 年份：2020 · DOI：10.1161/circulationaha.119.037661 · 被引用次数：259 · 研究领域：Cardiomyopathy and Myosin Studies、Genomics and Rare Diseases、Congenital heart defects research

BACKGROUND: Dilated cardiomyopathy (DCM) is genetically heterogeneous, with >100 purported disease genes tested in clinical laboratories. However, many genes were originally identified based on candidate-gene studies that did not adequately account for background population variation. Here we define the frequency of rare variation in 2538 patients with DCM across protein-coding regions of 56 commonly tested genes and compare this to both 912 confirmed healthy controls and a reference population of 60 706 individuals to identify clinically interpretable genes robustly associated with dominant monogenic DCM. METHODS: We used the TruSight Cardio sequencing panel to evaluate the burden of rare variants in 56 putative DCM genes in 1040 patients with DCM and 912 healthy volunteers processed with identical sequencing and bioinformatics pipelines. We further aggregated data from 1498 patients with DCM sequenced in diagnostic laboratories and the Exome Aggregation Consortium database for replication and meta-analysis. RESULTS: were significantly enriched in specific patient subsets, with the last 2 genes potentially contributing primarily to early-onset forms of DCM. Overall, rare variants in these 12 genes potentially explained 17% of cases in the outpatient clinic cohort representing a broad range of adult patients with DCM and 26% of cases in the diagnostic referral cohort enriched in familial and early-onset DCM. Although the absence of a significant excess in other genes cannot p...