Characterizing the morbid genome of ciliopathies.
Characterizing the morbid genome of ciliopathies.
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DOI：
10.1186/s13059-016-1099-5
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发表时间：
2016-11-28
期刊：
影响因子：
12.3
通讯作者：
Alkuraya FS
中科院分区：
文献类型：
--
作者：
Shaheen R;Szymanska K;Basu B;Patel N;Ewida N;Faqeih E;Al Hashem A;Derar N;Alsharif H;Aldahmesh MA;Alazami AM;Hashem M;Ibrahim N;Abdulwahab FM;Sonbul R;Alkuraya H;Alnemer M;Al Tala S;Al-Husain M;Morsy H;Seidahmed MZ;Meriki N;Al-Owain M;AlShahwan S;Tabarki B;Salih MA;Ciliopathy WorkingGroup;Faquih T;El-Kalioby M;Ueffing M;Boldt K;Logan CV;Parry DA;Al Tassan N;Monies D;Megarbane A;Abouelhoda M;Halees A;Johnson CA;Alkuraya FS
纤毛病是临床上多种原发性纤毛疾病。在了解这些遗传异质性疾病的分子基础方面已经取得了显着进展；然而，我们对其病态基因组、多效性和可变表达性的了解仍然不完整。我们对来自 265 个家庭的 371 名受影响个体组成的大型患者队列应用了基因组方法，这些患者的表型涵盖了整个纤毛病谱系。在 85% (225/265) 的家族中发现了先前描述的纤毛病基因的可能因果突变，增加了 32 个新的等位基因。与这些基因的完全渗透模型一致，我们发现除了我们的纤毛病队列和对照非纤毛病队列之间的因果变异之外，它们的“突变负荷”没有显着差异。基于具有一致纤毛病表型（梅克尔-格鲁伯综合征）的个体的独立功能缺失突变及其缺陷对纤毛信号传导的功能影响，我们队列的基因组分析进一步确定了编码硫醇异构酶的新型病态基因 TXNDC15 的突变。我们的研究还强调了七个新的候选基因（TRAPPC3、EXOC3L2、FAM98C、C17orf61、LRRCC1、NEK4 和 CELSR2），其中一些基因与纤毛发生建立了联系。最后，我们表明纤毛病的病态基因组包含许多始祖突变，其组合携带频率导致研究人群中的高疾病负担。我们的研究增加了我们对纤毛病病态基因组的了解。我们还提供迄今为止最有力的证据，支持巴代-比德尔综合征和其他纤毛病的经典孟德尔遗传。本文的在线版本 (doi:10.1186/s13059-016-1099-5) 包含补充材料，可供授权用户使用。
Ciliopathies are clinically diverse disorders of the primary cilium. Remarkable progress has been made in understanding the molecular basis of these genetically heterogeneous conditions; however, our knowledge of their morbid genome, pleiotropy, and variable expressivity remains incomplete. We applied genomic approaches on a large patient cohort of 371 affected individuals from 265 families, with phenotypes that span the entire ciliopathy spectrum. Likely causal mutations in previously described ciliopathy genes were identified in 85% (225/265) of the families, adding 32 novel alleles. Consistent with a fully penetrant model for these genes, we found no significant difference in their “mutation load” beyond the causal variants between our ciliopathy cohort and a control non-ciliopathy cohort. Genomic analysis of our cohort further identified mutations in a novel morbid gene TXNDC15, encoding a thiol isomerase, based on independent loss of function mutations in individuals with a consistent ciliopathy phenotype (Meckel-Gruber syndrome) and a functional effect of its deficiency on ciliary signaling. Our study also highlighted seven novel candidate genes (TRAPPC3, EXOC3L2, FAM98C, C17orf61, LRRCC1, NEK4, and CELSR2) some of which have established links to ciliogenesis. Finally, we show that the morbid genome of ciliopathies encompasses many founder mutations, the combined carrier frequency of which accounts for a high disease burden in the study population. Our study increases our understanding of the morbid genome of ciliopathies. We also provide the strongest evidence, to date, in support of the classical Mendelian inheritance of Bardet-Biedl syndrome and other ciliopathies. The online version of this article (doi:10.1186/s13059-016-1099-5) contains supplementary material, which is available to authorized users.
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影响因子：
12.3
作者：
Saudi Mendeliome Group
通讯作者：
Saudi Mendeliome Group
影响因子：
5.2
作者：
Abu-Safieh, Leen;Al-Anazi, Shamsa;Alkuraya, Fowzan S.
通讯作者：
Alkuraya, Fowzan S.
影响因子：
2
作者：
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通讯作者：
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影响因子：
2.3
作者：
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通讯作者：
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通讯作者：
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