Whole-Exome Sequencing Identifies Novel Variants for Tooth Agenesis
Whole-Exome Sequencing Identifies Novel Variants for Tooth Agenesis
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DOI：
10.1177/0022034517724149
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发表时间：
2018-01-01
影响因子：
7.6
通讯作者：
Letra, A.
中科院分区：
文献类型：
--
作者：
Dinckan, N.;Du, R.;Letra, A.
牙齿发育不全是人类常见的颅面异常，代表无法长出一颗或多颗恒牙。牙齿发育不全很复杂，据报道约有十几个基因的变异导致了病因。在这里，我们结合了全外显子组测序、基于芯片的基因分型和连锁分析，以确定 10 个多重土耳其家族中牙齿发育不全的候选疾病基因中的假定致病变异。 LRP6、DKK1、LAMA3 和 COL17A1 基因中的新纯合和杂合变体，以及 WNT10A 中的已知变体，被鉴定为可能导致孤立性牙齿发育不全的致病因素。 KREMEN1 的新变异被鉴定为可能在 2 个疑似牙齿发育不全综合征的家族中致病。在 2 个家族中，超过 1 个基因的变异与牙齿发育不全分离，表明存在寡基因遗传。错义变体的结构模型表明对编码的蛋白质有有害影响。 LRP6 中的 indel 变体 (c.3607+3_6del) 的功能分析表明，预测的 mRNA 会受到无义介导的衰减。我们的结果支持 WNT 通路基因在牙齿发育不全病因学中的重要作用，同时揭示了新的候选基因。此外，寡基因共分离暗示了发育过程中复杂的遗传和潜在复杂的基因产物相互作用，有助于提高对家族性牙齿发育不全的遗传病因学的理解。
Tooth agenesis is a common craniofacial abnormality in humans and represents failure to develop 1 or more permanent teeth. Tooth agenesis is complex, and variations in about a dozen genes have been reported as contributing to the etiology. Here, we combined whole-exome sequencing, array-based genotyping, and linkage analysis to identify putative pathogenic variants in candidate disease genes for tooth agenesis in 10 multiplex Turkish families. Novel homozygous and heterozygous variants in LRP6, DKK1, LAMA3, and COL17A1 genes, as well as known variants in WNT10A, were identified as likely pathogenic in isolated tooth agenesis. Novel variants in KREMEN1 were identified as likely pathogenic in 2 families with suspected syndromic tooth agenesis. Variants in more than 1 gene were identified segregating with tooth agenesis in 2 families, suggesting oligogenic inheritance. Structural modeling of missense variants suggests deleterious effects to the encoded proteins. Functional analysis of an indel variant (c.3607+3_6del) in LRP6 suggested that the predicted resulting mRNA is subject to nonsense-mediated decay. Our results support a major role for WNT pathways genes in the etiology of tooth agenesis while revealing new candidate genes. Moreover, oligogenic cosegregation was suggestive for complex inheritance and potentially complex gene product interactions during development, contributing to improved understanding of the genetic etiology of familial tooth agenesis.