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Mechanistic Modelling of Recessive Disease through Allelic Integration of Variant Effects

ABSTRACT: Interpreting variants in recessive diseases is difficult because clinical severity depends on the combined function of both alleles. Deep mutational scanning (DMS) experiments can provide functional measurements at scale, but their scores often relate nonlinearly to true biochemical activity. We developed a general method to infer enzymatic activities for thousands of variants by running two fitness assays at different expression levels and modelling the nonlinear activity–fitness relationship. These inferred activities allow computation of a biallelic pathogenicity score that captures the joint effect of two alleles. We applied this to adenylosuccinate lyase (ADSL), quantifying the effects of >8,000 coding variants in a yeast-based assay. The inferred activities separated pathogenic from benign alleles, and the biallelic score correlated strongly with biochemical measurements from patient-derived cells, outperforming existing predictors. This framework provides a broadly applicable strategy for mechanistic interpretation of variants in recessive enzymes.

ORGANISM(S): synthetic construct Saccharomyces cerevisiae

PROVIDER: GSE313314 | GEO | 2026/02/01

REPOSITORIES: GEO

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