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An evidence-based assessment of genes in dilated cardiomyopathy

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Title: An evidence-based assessment of genes in dilated cardiomyopathy
Authors: Jordan, E
Peterson, L
Ai, T
Asatryan, B
Bronicki, L
Brown, E
Celeghin, R
Edwards, M
Fan, J
Ingles, J
James, CA
Jarinova, O
Johnson, R
Judge, DP
Lahrouchi, N
Lekanne Deprez, RH
Lumbers, RT
Mazzarotto, F
Medeiros Domingo, A
Miller, RL
Morales, A
Murray, B
Peters, S
Pilichou, K
Protonotarios, A
Semsarian, C
Shah, P
Syrris, P
Thaxton, C
Van Tintelen, JP
Walsh, R
Wang, J
Ware, J
Hershberger, RE
Item Type: Journal Article
Abstract: Background: The cardiomyopathies, classically categorized as hypertrophic (HCM), dilated (DCM), and arrhythmogenic right ventricular (ARVC), each have a signature genetic theme. HCM and ARVC are largely understood as genetic diseases of sarcomere or desmosome proteins, respectively. In contrast, >250 genes spanning more than 10 gene ontologies have been implicated in DCM, representing a complex and diverse genetic architecture. To clarify this, a systematic curation of evidence to establish the relationship of genes with DCM was conducted. Methods: An international Panel with clinical and scientific expertise in DCM genetics evaluated evidence supporting monogenic relationships of genes with idiopathic DCM. The Panel utilized the ClinGen semi-quantitative gene-disease clinical validity classification framework with modifications for DCM genetics to classify genes into categories based on the strength of currently available evidence. Representation of DCM genes on clinically available genetic testing panels was evaluated. Results: Fifty-one genes with human genetic evidence were curated. Twelve genes (23%) from eight gene ontologies were classified as having definitive (BAG3, DES, FLNC, LMNA, MYH7, PLN, RBM20, SCN5A, TNNC1, TNNT2, TTN) or strong (DSP) evidence. Seven genes (14%) (ACTC1, ACTN2, JPH2, NEXN, TNNI3, TPM1, VCL) including two additional ontologies were classified as moderate evidence; these genes are likely to emerge as strong or definitive with additional evidence. Of these 19 genes, six were similarly classified for HCM and three for ARVC. Of the remaining 32 genes (63%), 25 (49%) had limited evidence, 4 (8%) were disputed, 2 (4%) had no disease relationship, and 1 (2%) was supported by animal model data only. Of 16 evaluated clinical genetic testing panels, most definitive genes were included, but panels also included numerous genes with minimal human evidence. Conclusions: In the curation of 51 genes, 19 had high evidence (12 definitive/strong; seven moderate). Notably, these 19 genes only explain a minority of cases, leaving the remainder of DCM genetic architecture incompletely addressed. Clinical genetic testing panels include most high evidence genes, however genes lacking robust evidence are also commonly included. We recommend that high evidence DCM genes be used for clinical practice and to exercise caution when interpreting variants in variable evidence DCM genes.
Issue Date: 6-Jul-2021
Date of Acceptance: 23-Mar-2021
URI: http://hdl.handle.net/10044/1/89064
DOI: 10.1161/CIRCULATIONAHA.120.053033
ISSN: 0009-7322
Publisher: Lippincott, Williams & Wilkins
Start Page: 7
End Page: 19
Journal / Book Title: Circulation
Volume: 144
Issue: 1
Copyright Statement: © 2021 The Authors. Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.
Sponsor/Funder: Wellcome Trust
British Heart Foundation
British Heart Foundation
Wellcome Trust
National Heart & Lung Institute Foundation
Funder's Grant Number: 107469/Z/15/Z
Keywords: cardiomyopathy
Cardiovascular System & Hematology
1102 Cardiorespiratory Medicine and Haematology
1103 Clinical Sciences
1117 Public Health and Health Services
Publication Status: Published
Online Publication Date: 2021-05-05
Appears in Collections:National Heart and Lung Institute
Institute of Clinical Sciences
Faculty of Medicine

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