Exploiting the Autozygome to Support Previously Published Mendelian Gene-Disease Associations: An Update.
Exploiting the Autozygome to Support Previously Published Mendelian Gene-Disease Associations: An Update.
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DOI：
10.3389/fgene.2020.580484
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发表时间：
2020
影响因子：
3.7
通讯作者：
Alkuraya FS
中科院分区：
文献类型：
--
作者：
Maddirevula S;Shamseldin HE;Sirr A;AlAbdi L;Lo RS;Ewida N;Al-Qahtani M;Hashem M;Abdulwahab F;Aboyousef O;Kaya N;Monies D;Salem MH;Al Harbi N;Aldhalaan HM;Alzaidan H;Almanea HM;Alsalamah AK;Al Mutairi F;Ismail S;Abdel-Salam GMH;Alhashem A;Asery A;Faqeih E;AlQassmi A;Al-Hamoudi W;Algoufi T;Shagrani M;Dudley AM;Alkuraya FS
为了促进孟德尔疾病背景下变异的正确分类，人们对标准化基因与疾病关联越来越感兴趣。一个关键的证据是对具有相似表型的无关个体的致病变异的独立观察。在这里，我们扩展了之前的努力，利用自合性的力量来产生纯合致病变异，这些变异由于其稀有性而很难在纯合状态下遇到。当在相容表型的背景下观察时，仅暂时与孟德尔疾病相关的基因中的此类变异的鉴定可以增加现有证据。在这项研究中，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，满足 ACMG 分类如果所涉及的基因已证实而不是暂时与疾病有联系，则为致病性/可能致病性。选择这些变体是因为它们被截短、具有引人注目的分离或受到强大的功能分析的支持，就像我们使用酵母模型进行验证的 DUT 变体一样。我们的研究结果支持了先前报道的这些基因与疾病的关联，并代表着向其确认迈出了一步。
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.
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DOI：
10.1038/s41436-018-0138-x
发表时间：
2019-03
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
--
作者：
Maddirevula S;Alzahrani F;Al-Owain M;Al Muhaizea MA;Kayyali HR;AlHashem A;Rahbeeni Z;Al-Otaibi M;Alzaidan HI;Balobaid A;El Khashab HY;Bubshait DK;Faden M;Yamani SA;Dabbagh O;Al-Mureikhi M;Jasser AA;Alsaif HS;Alluhaydan I;Seidahmed MZ;Alabbasi BH;Almogarri I;Kurdi W;Akleh H;Qari A;Al Tala SM;Alhomaidi S;Kentab AY;Salih MA;Chedrawi A;Alameer S;Tabarki B;Shamseldin HE;Patel N;Ibrahim N;Abdulwahab F;Samira M;Goljan E;Abouelhoda M;Meyer BF;Hashem M;Shaheen R;AlShahwan S;Alfadhel M;Ben-Omran T;Al-Qattan MM;Monies D;Alkuraya FS
通讯作者：
Alkuraya FS
影响因子：
11.4
作者：
GADSDEN, MH;MCINTOSH, EM;HAYNES, RH
通讯作者：
HAYNES, RH
影响因子：
20.3
作者：
Schramm, Elizabeth C.;Roumenina, Lubka T.;Fremeaux-Bacchi, Veronique
通讯作者：
Fremeaux-Bacchi, Veronique
影响因子：
8.8
作者：
Monies, Dorota;Maddirevula, Sateesh;Alkuraya, Fowzan S.
通讯作者：
Alkuraya, Fowzan S.
影响因子：
12.3
作者：
Maddirevula, Sateesh;Kuwahara, Hiroyuki;Alkuraya, Fowzan
通讯作者：
Alkuraya, Fowzan