![]() ![]() Variants in MYH7, LMNA, BAG3, TNNT2, TNNC1, PLN, ACTC1, NEXN, TPM1, and VCL were significantly enriched in specific patient subsets, with the last 2 genes potentially contributing primarily to early-onset forms of DCM. Truncating variants in TTN and DSP were associated with DCM in all comparisons. We further aggregated data from 1498 patients with DCM sequenced in diagnostic laboratories and the Exome Aggregation Consortium database for replication and meta-analysis. 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. 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. However, many genes were originally identified based on candidate-gene studies that did not adequately account for background population variation. 12 Department of Clinical and Experimental Cardiology, Heart Center, Amsterdam Cardiovascular Sciences, Amsterdam Universitair Medische Centra, University of Amsterdam, The Netherlands (R.W.).ĭilated cardiomyopathy (DCM) is genetically heterogeneous, with >100 purported disease genes tested in clinical laboratories.11 Duke-National University of Singapore Medical School (S.A.C.).10 Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston (B.F.).9 National Heart Centre Singapore (L.L.H.C., D.S., S.A.C.). ![]() 8 Radcliffe Department of Medicine, University of Oxford, United Kingdom (K.L.T., H.W.).7 Oxford Medical Genetics Laboratory, Oxford University Hospitals National Health Service Foundation Trust, The Churchill Hospital, United Kingdom (K.L.T.).6 Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, Cambridge, MA (A.Y.I.).A.d.M., T.J.W.D., D.P.O., S.A.C., J.S.W.), Imperial College London, United Kingdom. 5 Medical Research Council-London Institute of Medical Sciences (N.W.4 Department of Experimental and Clinical Medicine, University of Florence, Italy (F.M., I.O.).3 Cardiomyopathy Unit, Careggi University Hospital, Florence, Italy (F.M., I.O.).2 Cardiovascular Research Centre, Royal Brompton and Harefield National Health Service Foundation Trust, London, United Kingdom (F.M., U.T., R.J.B., W.M., A.W., N.W., R.G., E.M., L.E.F., M.A., P.I.T., E.E., A.J.B., A.A.P., A.M.R., P.J.R.B., S.K.P., S.A.C., J.S.W.). ![]()
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