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

• DOI: 10.1101/041111
• Publication Date: 2016-02-25T06:11:34Z
• Authors: Roddy Walsh; Kate L Thomson; James S Ware; Birgit H Funke; Jessica Woodley; Karen J McGuire; Francesco Mazzarotto; Edward Blair; Anneke Seller; Jenny C Taylor; Eric V Minikel; ; Daniel G MacArthur; Martin Farrall; Stuart A Cook; Hugh C Watkins
• Keywords: Mendelian inheritance

Abstract The accurate interpretation of variation in Mendelian disease genes has lagged behind data generation as sequencing become increasingly accessible. Ongoing large efforts present huge interpretive challenges, but also provide an invaluable opportunity to characterize the spectrum and importance rare variation. Here we analyze sequence from 7,855 clinical cardiomyopathy cases 60,706 ExAC reference samples better understand genetic a representative autosomal dominant disorder. We show that some previously reported important causes given cardiomyopathy, is not clinically informative there high likelihood false positive interpretation. By contrast, other genes, find diagnostic laboratories may be overly conservative when assessing variant pathogenicity. outline improved approaches for specific classes propose these will increase utility testing across range diseases. One Sentence Summary Comparing frequency very between patient cohorts genomic datasets enables reliable re-evaluation implicated more assessment likely pathogenicity different variants.