Using reported pathogenic variants to identify therapeutic opportunities
for genetic diseases
- Andrew Ressler,
- David Goldstein
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.