A power-based sliding window approach to evaluate the clinical impact of rare genetic variants in the nucleotide sequence or the spatial position of the folded protein

Abstract

Systematic determination of novel variant pathogenicity remains a major challenge, even when there is an established association between a gene and phenotype. Here we present Power Window (PW), a sliding window technique that identifies the impactful regions of a gene using population-scale clinico-genomic datasets. By sizing analysis windows on the number of variant carriers, rather than the number of variants or nucleotides, statistical power is held constant, enabling the localization of clinical phenotypes and removal of unassociated gene regions. The windows can be built by sliding across either the nucleotide sequence of the gene (through 1D space) or the positions of the amino acids in the folded protein (through 3D space).