Roddy Walsh | Search bioRxiv

bioRxiv2016

Using high-resolution variant frequencies to empower clinical genome interpretation

Whole exome and genome sequencing have transformed the discovery of genetic variants that cause human Mendelian disease, but discriminating pathogenic from benign variants remains a daunting challenge. Rarity is recognised as a necessary, although not sufficient, criterion for pathogenicity, but frequency cutoffs used in Mendelian analysis are often arbitrary and overly lenient. Recent very large reference datasets, such as the Exome Aggregation Consortium (ExAC), provide an unprecedented opportunity to obtain robust frequency estimates even for very rare variants. Here we present a statistical framework for the frequency-based filtering of candidate disease-causing variants, accounting for disease prevalence, genetic and allelic heterogeneity, inheritance mode, penetrance, and sampling variance in reference datasets. Using the example of cardiomyopathy, we show that our approach reduces by two-thirds the number of candidate variants under consideration in the average exome, and identifies 43 variants previously reported as pathogenic that can now be reclassified. We present precomputed allele frequency cutoffs for all variants in the ExAC dataset.

Genomics↗

bioRxiv2016

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

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

Genetics↗