Whole-Exome Sequencing of Discordant Monozygotic Twin Families for Identification of Candidate Genes for Microtia-Atresia.
Whole-Exome Sequencing of Discordant Monozygotic Twin Families for Identification of Candidate Genes for Microtia-Atresia.
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DOI：
10.3389/fgene.2020.568052
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发表时间：
2020
影响因子：
3.7
通讯作者：
Chen X
中科院分区：
文献类型：
--
作者：
Fan X;Ping L;Sun H;Chen Y;Wang P;Liu T;Jiang R;Zhang X;Chen X
我们使用来自双胞胎及其家庭的数据来探讨导致小耳畸形闭锁的遗传因素，特别是早期的孪生后变异，这些变异可能导致单卵双胞胎不一致的表型。六个家庭的单卵双胞胎不一致的先天性小耳畸形闭锁招募研究。这6例患者具有一致的单侧小耳畸形闭锁临床表型。对所有6对双胞胎及其父母进行全外显子组测序（WES）。应用家系分离和多种生物信息学方法对所有家系进行可疑突变的鉴定。突出显示了在至少两个家族中通常检测到的复发突变。通过桑格测序验证所有变体。进行基因本体（GO）分析以鉴定候选基因集和相关通路。拷贝数变异（CNV），连锁分析，关联分析和机器学习方法被用来分离候选突变，比较基因组学和结构建模工具被用来评估它们在小耳畸形闭锁发病中的潜在作用。我们的分析揭示了61个与小耳畸形闭锁相关的疑似突变基因。其中5个（HOXA 4、MUC 6、CHST 15、TBX 10和AMER1）包含至少出现在两个家族中的7个从头突变，这些突变先前已被报道为其他疾病的致病性。其中，HOXA 4（c.920A>C，p.H307P）被确定为小耳畸形闭锁的最可能致病变体。GO分析揭示了涉及11条通路的4个基因集，这些通路可能与疾病的潜在发病机制相关。在至少两个家族中检测到三个基因（UGT2B17、OVOS和KATNAL2）的CNV。连锁分析揭示了该疾病的13个额外标记，其中两个（FGFR1和EYA 1）通过机器学习分析被验证为该疾病的合理候选基因。综合遗传学和生物信息学分析的WES数据从6个家庭的不和谐的单卵双胞胎与小耳畸形闭锁，我们确定了多个候选基因，可能在孪生后发病的疾病。集体的发现提供了新的见解先天性小耳畸形闭锁的发病机制。
We used data from twins and their families to probe the genetic factors contributing to microtia-atresia, in particular, early post-twinning variations that potentially account for the discordant phenotypes of monozygotic twin pairs. Six families of monozygotic twins discordant for congenital microtia-atresia were recruited for study. The six patients shared a consistent clinical phenotype of unilateral microtia-atresia. Whole-exome sequencing (WES) was performed for all six twin pairs and their parents. Family segregation and multiple bioinformatics methods were applied to identify suspicious mutations in all families. Recurring mutations commonly detected in at least two families were highlighted. All variants were validated via Sanger sequencing. Gene Ontology (GO) analysis was performed to identify candidate gene sets and related pathways. Copy number variation (CNV), linkage analysis, association analysis and machine learning methods were additionally applied to isolate candidate mutations, and comparative genomics and structural modeling tools used to evaluate their potential roles in onset of microtia-atresia. Our analyses revealed 61 genes with suspected mutations associated with microtia-atresia. Five (HOXA4, MUC6, CHST15, TBX10, and AMER1) contained 7 de novo mutations that appeared in at least two families, which have been previously reported as pathogenic for other diseases. Among these, HOXA4 (c.920A>C, p.H307P) was determined as the most likely pathogenic variant for microtia-atresia. GO analysis revealed four gene sets involving 11 pathways potentially related to underlying pathogenesis of the disease. CNVs in three genes (UGT2B17, OVOS, and KATNAL2) were detected in at least two families. Linkage analysis disclosed 13 extra markers for the disease, of which two (FGFR1 and EYA1) were validated via machine learning analysis as plausible candidate genes for the disease. Based on comprehensive genetic and bioinformatic analyses of WES data from six families of discordant monozygotic twins with microtia-atresia, we identified multiple candidate genes that may function in post-twinning onset of the disease. The collective findings provide novel insights into the pathogenesis of congenital microtia-atresia.
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影响因子：
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作者：
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