Abstract
PurposeWhole-exome and whole-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 recognized 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.MethodsWe 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.ResultsUsing the example of cardiomyopathy, we show that our approach reduces by two-thirds the number of candidate variants under consideration in the average exome, without removing true pathogenic variants (false-positive rate<0.001).ConclusionWe outline a statistically robust framework for assessing whether a variant is “too common” to be causative for a Mendelian disorder of interest. We present precomputed allele frequency cutoffs for all variants in the ExAC dataset.
Highlights
Whole-exome and whole-genome sequencing have been instrumental in identifying causal variants in Mendelian disease patients.[1]
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, without removing true pathogenic variants
We present precomputed allele frequency cutoffs for all variants in the Exome Aggregation Consortium (ExAC) dataset
Summary
Whole-exome and whole-genome sequencing have been instrumental in identifying causal variants in Mendelian disease patients.[1] As every individual harbors ~ 12,000–14,000 predicted protein-altering variants,[2] distinguishing diseasecausing variants from benign bystanders is perhaps the principal challenge in contemporary clinical genetics. There exists considerable ambiguity around what AF should be considered “too common,” with the lenient values of 1 and 0.1% often invoked as conservative frequency cutoffs for recessive and dominant diseases respectively.[5] Population genetics, dictates that severe diseasecausing variants must be much rarer than these cutoffs, except in cases of bottlenecked populations, balancing selection, or other special circumstances.[6,7]
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