GeVIR is a continuous gene-level metric that uses variant distribution patterns to prioritize disease candidate genes

摘要

With large-scale population sequencing projects gathering pace, there is a need for strategies that advance disease gene prioritization(1,2). Metrics that provide information about a gene and its ability to tolerate protein-altering variation can aid in clinical interpretation of human genomes and can advance disease gene discovery(1-4). Previous reported methods analyzed the total variant load in a gene(1-4), but did not analyze the distribution pattern of variants within a gene. Using data from 138,632 exome and genome sequences(2), we developed gene variation intolerance rank (GeVIR), a continuous gene-level metric for 19,361 genes that is able to prioritize both dominant and recessive Mendelian disease genes(5), that outperforms missense constraint metrics(3) and that is comparable-but complementary-to loss-of-function (LOF) constraint metrics(2). GeVIR is also able to prioritize short genes, for which LOF constraint cannot be estimated with confidence(2). The majority of the most intolerant genes identified here have no defined phenotype and are candidates for severe dominant disorders.