A gene-centric strategy for identifying disease-causing rare variants in dilated cardiomyopathy

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Title: A gene-centric strategy for identifying disease-causing rare variants in dilated cardiomyopathy
Authors: Horvat, C
Johnson, R
Lam, L
Munro, J
Mazzarotto, F
Roberts, A
Herman, D
Parfenov, M
Haghighli, A
Macdonough, B
DePalma, S
Keogh, A
Macdonald, P
Hayward, C
Roberts, A
Barton, PJR
Felkin, L
Giannoulatou, E
Cook, S
Seidman, J
Siedman, C
Fatkin, D
Item Type: Journal Article
Abstract: Purpose We evaluated strategies for identifying disease-causing variants in genetic testing for dilated cardiomyopathy (DCM). Methods Cardiomyopathy gene panel testing was performed in 532 DCM patients and 527 healthy control subjects. Rare variants in 41 genes were stratified using variant-level and gene-level characteristics. Results A majority of DCM cases and controls carried rare protein-altering cardiomyopathy gene variants. Variant-level characteristics alone had limited discriminative value. Differentiation between groups was substantially improved by addition of gene-level information that incorporated ranking of genes based on literature evidence for disease association. The odds of DCM were increased to nearly 9-fold for truncating variants or high-impact missense variants in the subset of 14 genes that had the strongest biological links to DCM (P <0.0001). For some of these genes, DCM-associated variants appeared to be clustered in key protein functional domains. Multiple rare variants were present in many family probands, however, there was generally only one “driver” pathogenic variant that cosegregated with disease. Conclusion Rare variants in cardiomyopathy genes can be effectively stratified by combining variant-level and gene-level information. Prioritization of genes based on their a priori likelihood of disease causation is a key factor in identifying clinically actionable variants in cardiac genetic testing.
Issue Date: 1-Jan-2019
Date of Acceptance: 22-Mar-2018
URI: http://hdl.handle.net/10044/1/58471
DOI: https://dx.doi.org/10.1038/s41436-018-0036-2
ISSN: 1098-3600
Publisher: Nature Publishing Group
Start Page: 133
End Page: 143
Journal / Book Title: Genetics in Medicine
Volume: 21
Issue: 1
Copyright Statement: © 2019 Springer Nature Publishing AG
Sponsor/Funder: British Heart Foundation
Fondation Leducq
Fondation Leducq
Royal Brompton & Harefield NHS Foundation Trust
Funder's Grant Number: SP/10/10/28431
11 CVD-01
11 CVD-01
RBHT6179
Keywords: Science & Technology
Life Sciences & Biomedicine
Genetics & Heredity
Dilated cardiomyopathy
pathogenic variant Genetic testing
Next-generation sequencing
SODIUM-CHANNEL NA(V)1.5
SCN5A MUTATION
HEART-FAILURE
ASSOCIATION
SERVER
TITIN
BAG3
Dilated cardiomyopathy
Genetic testing
Next-generation sequencing
pathogenic variant
Cardiomyopathy, Dilated
Female
Genetic Predisposition to Disease
Genetic Testing
High-Throughput Nucleotide Sequencing
Humans
Male
Middle Aged
Mutation, Missense
Pedigree
Rare Diseases
Humans
Cardiomyopathy, Dilated
Genetic Predisposition to Disease
Rare Diseases
Pedigree
Mutation, Missense
Middle Aged
Female
Male
Genetic Testing
High-Throughput Nucleotide Sequencing
Genetics & Heredity
0604 Genetics
1103 Clinical Sciences
Publication Status: Published
Online Publication Date: 2018-06-11
Appears in Collections:National Heart and Lung Institute
Faculty of Medicine



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