Maddirevula Sateesh, Shamseldin Hanan E, Sirr Amy, AlAbdi Lama, Lo Russell S, Ewida Nour, Al-Qahtani Mashael, Hashem Mais, Abdulwahab Firdous, Aboyousef Omar, Kaya Namik, Monies Dorota, Salem May H, Al Harbi Naffaa, Aldhalaan Hesham M, Alzaidan Hamad, Almanea Hadeel M, Alsalamah Abrar K, Al Mutairi Fuad, Ismail Samira, Abdel-Salam Ghada M H, Alhashem Amal, Asery Ali, Faqeih Eissa, AlQassmi Amal, Al-Hamoudi Waleed, Algoufi Talal, Shagrani Mohammad, Dudley Aimée M, Alkuraya Fowzan S
Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
Pacific Northwest Research Institute, Seattle, WA, United States.
Front Genet. 2020 Dec 31;11:580484. doi: 10.3389/fgene.2020.580484. eCollection 2020.
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 (, and ) 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 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.
为了便于在孟德尔疾病背景下对变异进行正确分类，人们对标准化基因与疾病的关联越来越感兴趣。一个关键的证据线索是在具有相似表型的无关个体中独立观察到致病变异。在此，我们扩展了我们之前的工作，利用纯合性的力量来产生纯合致病变异，由于其罕见性，这些变异在纯合状态下很难遇到。在与孟德尔疾病只有初步关联的基因中鉴定出此类变异，如果在兼容表型的背景下观察到，可增加现有证据。在本研究中，我们报告了18个基因（、和）中的20个纯合变异，如果所涉及的基因与疾病的联系得到确认而非初步关联，这些变异符合美国医学遗传学与基因组学学会（ACMG）对致病/可能致病的分类。选择这些变异是因为它们是截短型的、具有显著分离现象的奠基者变异，或者得到了强大功能试验的支持，比如我们使用酵母模型对变异进行验证的情况。我们的发现支持了之前报道的这些基因与疾病的关联，并朝着对它们的确认迈出了一步。
