Linking disease genotypes to phenotype

Abstract

Human Genetics The penetrance of a genetic variant is the degree to which a specific genetic change affects an individual's phenotype. However, it is not clear why a specific pathogenic mutation exhibits an unpredictable phenotype among individuals. Castel et al. examined the genomes and expression of RNA across individuals and found that deleterious mutations affecting protein-coding genes are more likely to be linked to regulatory elements that lower the expression of the pathogenic gene—hence lowering the overall penetrance of the mutation. However, relative to unaffected people, the overall penetrance was higher in individuals with cancer and autism. These results suggest that the joint effects of regulatory and coding mutations are subject to purifying selection to reduce penetrance. Nat. Genet. 10.1038/s41588-018-0192-y (2018).