Prevalence of loss-of-function, gain-of-function and dominant-negative mechanisms across genetic disease phenotypes.

ABSTRACT: Molecular disease mechanisms caused by mutations in protein-coding regions are diverse, but they can be broadly categorised into loss-of-function, gain-of-function and dominant-negative effects. Accurately predicting these mechanisms is important, since therapeutic strategies can exploit these mechanisms. Computational predictors tend to perform less well at the identification of pathogenic gain-of-function and dominant-negative variants. Here, we develop a protein structure-based missense loss-of-function likelihood score that can separate recessive loss of function and dominant loss of function from alternative disease mechanisms. Using missense loss-of-function scores, we estimate the prevalence of molecular mechanisms across 2,837 phenotypes in 1,979 Mendelian disease genes, finding th

SUBMITTER: Badonyi M 

PROVIDER: S-EPMC12462468 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature