Unified views on variant impact across many diseases

Abstract

Genomic studies of human disorders are often performed by distinct research communities (i.e., focused on rare diseases, common diseases, or cancer). Despite underlying differences in the mechanistic origin of different disease categories, these studies share the goal of identifying causal genomic events that are critical for the clinical manifestation of the disease phenotype. Moreover, these studies face common challenges, including understanding the complex genetic architecture of the disease, deciphering the impact of variants on multiple scales, and interpreting noncoding mutations. Here, we highlight these challenges in depth and argue that properly addressing them will require a more unified vocabulary and approach across disease communities. Toward this goal, we present a unified perspective on relating variant impact to various genomic disorders.

Keywords: cumulative impact; driver mutations; genomic structural variations; mutation impact; regulatory mutations; variant interpretation.