Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples

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Title: Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples
Authors: Walsh, R
Thomson, KL
Ware, JS
Funke, BH
Woodley, J
McGuire, KJ
Mazzarotto, F
Blair, E
Seller, A
Taylor, JC
Minikel, EV
Exome Aggregation Consortium
MacArthur, DG
Farrall, M
Cook, SA
Watkins, H
Item Type: Journal Article
Abstract: PURPOSE: The accurate interpretation of variation in Mendelian disease genes has lagged behind data generation as sequencing has become increasingly accessible. Ongoing large sequencing efforts present huge interpretive challenges, but they also provide an invaluable opportunity to characterize the spectrum and importance of rare variation. METHODS: We analyzed sequence data from 7,855 clinical cardiomyopathy cases and 60,706 Exome Aggregation Consortium (ExAC) reference samples to obtain a better understanding of genetic variation in a representative autosomal dominant disorder. RESULTS: We found that in some genes previously reported as important causes of a given cardiomyopathy, rare variation is not clinically informative because there is an unacceptably high likelihood of false-positive interpretation. By contrast, in other genes, we find that diagnostic laboratories may be overly conservative when assessing variant pathogenicity. CONCLUSIONS: We outline improved analytical approaches that evaluate which genes and variant classes are interpretable and propose that these will increase the clinical utility of testing across a range of Mendelian diseases.Genet Med advance online publication 17 August 2016Genetics in Medicine (2016); doi:10.1038/gim.2016.90.
Issue Date: 17-Aug-2016
Date of Acceptance: 10-May-2016
ISSN: 1530-0366
Publisher: Nature Publishing Group
Start Page: 192
End Page: 203
Journal / Book Title: Genetics in Medicine
Volume: 19
Copyright Statement: © R Walsh et al. (2016). This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit
Sponsor/Funder: Wellcome Trust
Department of Health
Wellcome Trust
Funder's Grant Number: HICF-R6-373
Keywords: Science & Technology
Life Sciences & Biomedicine
Genetics & Heredity
clinical genetics
Exome Aggregation Consortium
inherited cardiomyopathy
Mendelian genetics
variation interpretation
0604 Genetics
1103 Clinical Sciences
Publication Status: Published
Open Access location: http://spiral/
Appears in Collections:National Heart and Lung Institute
Faculty of Medicine

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