Mechanistic modeling of recessive disease through allelic integration of variant effects (opens in new tab)

Recessive diseases arise from the combined effects of two alleles, yet most variant interpretation methods consider variants individually. Çubuk et al. map more than 8,000 variants in the recessive enzyme adenylosuccinate lyase (ADSL) by using deep mutational scanning and infer enzymatic activity from nonlinear modeling of fitness measurements. By combining allelic activities into bi-allelic scores, the authors show improved prediction of biochemical activity and patient phenotypes. This work...