Institute for Genomic Medicine, Columbia University, New York, New York, USA.
Mol Genet Genomic Med. 2023 Jan;11(1):e2097. doi: 10.1002/mgg3.2097. Epub 2022 Nov 14.
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.
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.
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.
We suggest a set of 16 genes suitable for drug developmental efforts utilizing direct inhibition.
遗传疾病的药物研发策略严重依赖于对致病变异如何导致疾病的确切认识。对于一些研究充分的基因，致病变异的直接效应作为功能丧失、功能获得或超显性，或两者的组合已有详细记录。然而，对于许多基因，甚至变异的效应方向仍不清楚。根据致病性变异是功能丧失还是功能获得对孟德尔疾病基因进行分类，将直接为药物研发策略提供信息。
我们利用最近报道的致病性变异的急剧增加，提供了一种推断致病性变异效应方向的新方法。具体来说，我们量化了报道的致病性错义变异与功能丧失变异的比例。
我们首先表明，对于许多导致显性孟德尔疾病的基因，报道的致病性错义变异的比例可以诊断该基因是通过功能丧失还是功能获得，还是两者的组合导致疾病。其次，我们确定了一组似乎主要或完全通过功能获得或超显性致病性变异导致疾病的基因。
我们建议了一组 16 个适合利用直接抑制进行药物开发的基因。
