Table_1_Exploiting the Autozygome to Support Previously Published Mendelian Gene-Disease Associations: An Update.xlsx

There is a growing interest in standardizing gene-disease associations for the purpose of facilitating the proper classification of variants in the context of Mendelian diseases. One key line of evidence is the independent observation of pathogenic variants in unrelated individuals with similar phenotypes. Here, we expand on our previous effort to exploit the power of autozygosity to produce homozygous pathogenic variants that are otherwise very difficult to encounter in the homozygous state due to their rarity. The identification of such variants in genes with only tentative associations to Mendelian diseases can add to the existing evidence when observed in the context of compatible phenotypes. In this study, we report 20 homozygous variants in 18 genes (ADAMTS18, ARNT2, ASTN1, C3, DMBX1, DUT, GABRB3, GM2A, KIF12, LOXL3, NUP160, PTRHD1, RAP1GDS1, RHOBTB2, SIGMAR1, SPAST, TENM3, and WASHC5) that satisfy the ACMG classification for pathogenic/likely pathogenic if the involved genes had confirmed rather than tentative links to diseases. These variants were selected because they were truncating, founder with compelling segregation or supported by robust functional assays as with the DUT variant that we present its validation using yeast model. Our findings support the previously reported disease associations for these genes and represent a step toward their confirmation.

对于标准化基因-疾病关联，以促进孟德尔疾病中变异的适当分类，业已呈现出日益增长的兴趣。一项关键证据是，在具有相似表型的非亲缘个体中独立观察到致病性变异。在此，我们进一步拓展先前的努力，旨在利用自纯性的力量产生同型纯合致病性变异，这类变异在纯合状态下由于罕见性而难以遇到。在那些仅与孟德尔疾病存在试探性关联的基因中，此类变异的识别，当其在兼容表型背景下观察到时，可以补充现有证据。在本研究中，我们报告了18个基因（ADAMTS18、ARNT2、ASTN1、C3、DMBX1、DUT、GABRB3、GM2A、KIF12、LOXL3、NUP160、PTRHD1、RAP1GDS1、RHOBTB2、SIGMAR1、SPAST、TENM3和WASHC5）中的20个同型纯合变异，若涉及基因与疾病之间存在确凿而非试探性联系，则这些变异符合ACMG的分类标准，属于致病性/可能致病性。这些变异之所以被选中，是因为它们是截断型、奠基者具有有力的分离或支持强有力的功能测试，例如我们呈现的DUT变异，我们使用酵母模型对其进行了验证。我们的发现支持了先前报道的这些基因与疾病关联，并代表了证实这些关联的一个步骤。