期刊
GENETICS IN MEDICINE
卷 19, 期 2, 页码 192-203出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/gim.2016.90
关键词
clinical genetics; Exome Aggregation Consortium; inherited cardiomyopathy; Mendelian genetics; variation interpretation
资金
- NIHR Oxford Biomedical Research Centre
- NIHR Biomedical Research Unit in Cardiovascular Disease at the Royal Brompton & Harefield NHS Foundation Trust
- Imperial College London
- Wellcome Trust
- Fondation Leducq
- Tanoto Foundation
- SingHealth Duke-NUS Institute of Precision Medicine (PRISM)
- Medical Research Council
- Academy of Medical Sciences
- British Heart Foundation
- Arthritis Research UK
- National Medical Research Council (NMRC) Singapore
- National Institute for Health Research (NIHR) [NIHR-HCS-D13-04-006]
- Wellcome Trust [090532/Z/09/Z]
- BHF Centre of Research Excellence in Oxford [RE/13/1/30181]
- National Institutes of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health [U54DK105566]
- MRC [MC_UP_1102/20, MC_U120085815] Funding Source: UKRI
- British Heart Foundation [FS/13/13/29819, SP/10/10/28431, RG/12/16/29939] Funding Source: researchfish
- Medical Research Council [MC_UP_1102/20, MC_U120085815] Funding Source: researchfish
- National Institute for Health Research [NIHR-HCS-D13-04-006, NF-SI-0513-10087] Funding Source: researchfish
- Wellcome Trust [107469/Z/15/Z] Funding Source: researchfish
- National Institutes of Health Research (NIHR) [NIHR-HCS-D13-04-006] Funding Source: National Institutes of Health Research (NIHR)
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 likelihodd of false positive interpretation. By contrast, in other genes, we find that diagnostic laboratories maybe 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.
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