Using reported pathogenic variants to identify therapeutic opportunities for genetic diseases.

ABSTRACT:

Purpose

Drug development strategies for genetic diseases depend critically on accurate knowledge of how pathogenic variants cause disease. For some well-studied genes, the direct effects of pathogenic variants are well documented as loss-of-function, gain-of-function or hypermorphic, or a combination of the two. For many genes, however, even the direction of effect of variants remains unclear. Classification of Mendelian disease genes in terms of whether pathogenic variants are loss- or gain-of-function would directly inform drug development strategies.

Methods

We leveraged the recent dramatic increase in reported pathogenic variants to provide a novel approach to inferring the direction of effect of pathogenic variants. Specifically, we quantify the ratio of reported pathogenic variants that are missense compared to loss-of-function.

Results

We first show that for many genes that cause dominant Mendelian disease, the ratio of reported pathogenic missense variants is diagnostic of whether the gene causes disease through loss- or gain-of-function, or a combination. Second, we identify a set of genes that appear to cause disease largely or entirely through gain-of-function or hypermorphic pathogenic variants.

Conclusions

We suggest a set of 16 genes suitable for drug developmental efforts utilizing direct inhibition.

SUBMITTER: Ressler AK 

PROVIDER: S-EPMC9834146 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature