The spectrum of gene intolerance to variation: Insights from a rare disease cohort

Abstract

Deciphering the spectrum of intolerance to loss-of-function (LoF) variation helps identify genes that are critical at various stages of development and hierarchical levels of organisation. We have previously combined cell and mouse viability screens for single-gene knockouts, to summarise this spectrum into discrete categories, Full Spectrum of Intolerance to Loss-of-function (FUSIL), from genes essential for cell proliferation to those where LoF has no phenotypic impact. Here, we expand on this analysis to uncover distinct patterns in gene expression across developmental stages in both mouse and human within these categories, as well as gene sequence and evolutionary features, protein functional classes, and disease associations. Further, by analysing data from diagnosed patients in a rare disease cohort, we gain insights into the relationships between variant de novo status, molecular consequence, mode of inheritance, and type of disorder in the FUSIL categories. These associations facilitate the identification of predicted pathogenic variants in genes not currently linked to Mendelian conditions.