Table_3_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.

近年来，对于标准化基因-疾病关联的兴趣日益浓厚，旨在促进孟德尔疾病中变异的恰当分类。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显性来产生纯合致病性变异的努力，这些变异在纯合状态下因罕见性而难以遇到。在具有与孟德尔疾病仅存在试探性关联的基因中识别此类变异，当其在相符的表型背景下被观察到时，可以增加现有证据。在本研究中，我们报道了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，如果涉及的基因与疾病而非试探性关联得到确认，这些变异符合ACMG的分类标准为致病性/可能致病性。这些变异之所以被选中，是因为它们是截断型、创始者与强有力的分离相关联，或由如DUT变异所支持的稳健的功能检测所支持，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，并代表了向其确认迈出的重要一步。