Re-evaluating the genetic contribution of monogenic dilated cardiomyopathy

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Title: Re-evaluating the genetic contribution of monogenic dilated cardiomyopathy
Authors: Mazzarotto, F
Tayal, U
Buchan, RJ
Midwinter, W
Wilk, A
Whiffin, N
Govind, R
Mazaika, E
De Marvao, A
Dawes, T
Felkin, LE
Ahmad, M
Theotokis, PI
Edwards, E
Ing, AI
Thomson, KL
Chan, LLH
Sim, D
Baksi, AJ
Pantazis, A
Roberts, AM
Watkins, H
Funke, B
O'Regan, D
Olivotto, I
Barton, PJR
Prasad, SK
Cook, SA
Ware, JS
Walsh, R
Item Type: Journal Article
Abstract: 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 DCM patients 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 in order 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 DCM patients and 912 healthy volunteers processed with identical sequencing and bioinformatics pipelines. We further aggregated data from 1498 DCM patients sequenced in diagnostic laboratories and the ExAC database for replication and meta-analysis. Results: Truncating variants in TTN and DSP were associated with DCM in all comparisons. 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. Overall, rare variants in these 12 genes potentially explained 17% of cases in the outpatient clinic cohort representing a broad range of adult DCM patients and 26% of cases in the diagnostic referral cohort enriched in familial and early-onset DCM. Whilst the absence of a significant excess in other genes cannot preclude a limited role in disease, such genes have limited diagnostic value since novel variants will be uninterpretable and their diagnostic yield is minimal. Conclusion: In the largest sequenced DCM cohort yet described, we observe robust disease association with 12 genes, highlighting their importance in DCM and translating into high interpretability in diagnostic testing. The other genes analysed here will need to be rigorously evaluated in ongoing curation efforts to determine their validity as Mendelian DCM genes but have limited value in diagnostic testing in DCM at present. This data will contribute to community gene curation efforts and will reduce erroneous and inconclusive findings in diagnostic testing.
Date of Acceptance: 14-Nov-2019
ISSN: 0009-7322
Publisher: American Heart Association
Journal / Book Title: Circulation
Copyright Statement: This paper is embargoed until publication. Once published it will be available fully open access.
Sponsor/Funder: British Heart Foundation
Wellcome Trust
British Heart Foundation
Medical Research Council (MRC)
Fondation Leducq
Fondation Leducq
Department of Health
Imperial College Healthcare NHS Trust- BRC Funding
British Heart Foundation
Imperial College Healthcare NHS Trust- BRC Funding
Commission of the European Communities
Wellcome Trust
British Heart Foundation
Rosetrees Trust
British Heart Foundation
Funder's Grant Number: SP/10/10/28431
11 CVD-01
11 CVD-01
Keywords: Cardiovascular System & Hematology
1103 Clinical Sciences
1102 Cardiorespiratory Medicine and Haematology
1117 Public Health and Health Services
Publication Status: Accepted
Embargo Date: publication subject to indefinite embargo
Appears in Collections:Clinical Sciences
Imaging Sciences
National Heart and Lung Institute
Faculty of Medicine

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