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

Mihaly Badonyi () and Joseph A. Marsh ()
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Mihaly Badonyi: University of Edinburgh
Joseph A. Marsh: University of Edinburgh

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: 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 that dominant-negative and gain-of-function mechanisms account for 48% of phenotypes in dominant genes. Applying missense loss-of-function scores to genes with multiple phenotypes reveals widespread intragenic mechanistic heterogeneity, with 43% of dominant and 49% of mixed-inheritance genes harbouring both loss-of-function and non-loss-of-function mechanisms. Furthermore, we show that combining missense loss-of-function scores with phenotype semantic similarity enables the prioritisation of dominant-negative mechanisms in mixed-inheritance genes. Our structure-based approach, accessible via a Google Colab notebook, offers a scalable tool for predicting disease mechanisms and advancing personalised medicine.

Date: 2025
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DOI: 10.1038/s41467-025-63234-3

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