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Title: Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples
Authors: Walsh R.
Thomson K.L.
Ware J.S.
Funke B.H.
Woodley J.
McGuire K.J.
Mazzarotto F.
Blair E.
Seller A.
Taylor J.C.
Minikel E.V.
MacArthur D.G.
Farrall M.
Cook S.A. 
Watkins H.
Keywords: Clinical genetics
Exome Aggregation Consortium
Inherited cardiomyopathy
Mendelian genetics
Variation interpretation
Issue Date: 2017
Publisher: Nature Publishing Group
Citation: Walsh R., Thomson K.L., Ware J.S., Funke B.H., Woodley J., McGuire K.J., Mazzarotto F., Blair E., Seller A., Taylor J.C., Minikel E.V., MacArthur D.G., Farrall M., Cook S.A., Watkins H. (2017). Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genetics in Medicine 19 (2) : 192-203. ScholarBank@NUS Repository.
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. © American College of Medical Genetics and Genomics.
Source Title: Genetics in Medicine
ISSN: 10983600
DOI: 10.1038/gim.2016.90
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