Table_2_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.

对基因疾病关联进行标准化的兴趣日益浓厚，旨在促进孟德尔疾病中变异的正确分类。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，我们进一步拓展了先前利用自交能力产生纯合致病性变异的努力，这些变异在纯合状态下由于罕见性而难以遇到。在仅与孟德尔疾病有试探性关联的基因中识别出此类变异，当它们在符合的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个纯合变异，这些变异如果涉及的基因与疾病有确凿而非试探性联系，则符合ACMG的分类标准为致病性/可能致病性。这些变异被选中，是因为它们是截断型、具有令人信服的分离或由稳健的功能测试支持，例如我们用酵母模型验证的DUT变异。我们的发现支持了先前报告的这些基因与疾病的相关性，并代表了对这些基因确认步骤的推进。