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A gene-centric strategy for identifying disease-causing rare variants in dilated cardiomyopathy
File | Description | Size | Format | |
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GIM-D-17-00727_R2.pdf | Accepted version | 23.3 MB | Adobe PDF | View/Open |
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: | Institute of Clinical Sciences Institute of Clinical Sciences |