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

Genet Med
Authors
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 19 2, 192-203.

Year of Publication
2017
Journal
Genet Med
Volume
19
Issue
2
Pages
192-203
Date Published
2017 Feb
ISSN
1530-0366
DOI
10.1038/gim.2016.90
PubMed ID
27532257
PubMed Central ID
PMC5116235
Links
Grant list
U54 DK105566 / DK / NIDDK NIH HHS / United States