Exome Sequencing in Individuals with Isolated Biliary Atresia.
Exome Sequencing in Individuals with Isolated Biliary Atresia.
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孤立性胆道闭锁个体的外显子组测序。
DOI：
10.1038/s41598-020-59379-4
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发表时间：
2020
影响因子：
4.6
通讯作者：
Devoto,Marcella
中科院分区：
文献类型：
--
作者：
Rajagopalan,Ramakrishnan;Tsai,EllenA;Grochowski,ChristopherM;Kelly,SusanM;Loomes,KathleenM;Spinner,NancyB;Devoto,Marcella
胆道闭锁是一种严重的小儿肝脏疾病，导致肝外胆道系统坏死性炎症闭塞。BA在出生后的最初几个月内表现为孤立的发现或其他综合征特征。孤立性BA的病因学尚不清楚，有证据表明存在感染、环境和遗传风险因素。然而，到目前为止，还没有确定的致病基因在人类中孤立的BA，是否单基因缺陷发挥主要作用的问题仍然悬而未决。我们对101名患有孤立性BA的欧洲血统北美患者（包括30名亲子三人组）进行了外显子组测序，并考虑了几种实验设计来识别可能参与该疾病的潜在有害蛋白质改变变体。在仅病例分析中，我们没有发现两个以上先证者共有变异的基因，并且使用病例-病例对照设计对罕见变异进行的负担测试没有产生显著结果。在对30个单纯性家系（患者和父母三人组）的三人组分析中，我们在66个基因中鉴定出66个新变异体，包括STIP 1和REV 1中的潜在有害变异体。STIP 1是热休克蛋白HSP 90的辅助分子伴侣，在酵母、果蝇和哺乳动物中具有多种功能，包括应激反应。REV 1是DNA修复途径中的关键分子，与HSP 90相互作用。总之，我们的研究结果不支持假设，一个简单的遗传模型是负责大多数情况下孤立BA。我们在与进化上保守的应激反应（STIP 1和REV 1）相关的基因中发现了新的变异体，这表明探索遗传易感性和环境暴露如何相互作用导致BA是必要的。
Biliary atresia (BA) is a severe pediatric liver disease resulting in necroinflammatory obliteration of the extrahepatic biliary tree. BA presents within the first few months of life as either an isolated finding or with additional syndromic features. The etiology of isolated BA is unknown, with evidence for infectious, environmental, and genetic risk factors described. However, to date, there are no definitive causal genes identified for isolated BA in humans, and the question of whether single gene defects play a major role remains open. We performed exome-sequencing in 101 North American patients of European descent with isolated BA (including 30 parent-child trios) and considered several experimental designs to identify potentially deleterious protein-altering variants that may be involved in the disease. In a case-only analysis, we did not identify genes with variants shared among more than two probands, and burden tests of rare variants using a case-case control design did not yield significant results. In the trio analysis of 30 simplex families (patient and parent trios), we identified 66de novovariants in 66 genes including potentially deleterious variants inSTIP1andREV1. STIP1 is a co-chaperone for the heat-shock protein, HSP90, and has been shown to have diverse functions in yeast, flies and mammals, including stress-responses. REV1 is known to be a key player in DNA repair pathway and to interact with HSP90. In conclusion, our results do not support the hypothesis that a simple genetic model is responsible for the majority of cases of isolated BA. Our finding ofde novovariants in genes linked to evolutionarily conserved stress responses (STIP1andREV1) suggests that exploration of how genetic susceptibility and environmental exposure may interact to cause BA is warranted.