Mutation analysis in patients with nonsyndromic tooth agenesis using exome sequencing.
Mutation analysis in patients with nonsyndromic tooth agenesis using exome sequencing.
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DOI：
10.1002/mgg3.2045
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发表时间：
2022-10
影响因子：
2
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中科院分区：
文献类型：
--
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牙齿发育不全（TA）是一种先天性异常，可以表现为综合征或非综合征。考虑到其复杂的遗传病因，本研究的目的是发现非综合征型TA患者的致病突变体，并分析这些突变体的特点。对来自43个非综合征性TA家系的72例患者进行外显子组测序，以检测致病性变异。使用桑格测序验证所有候选变体。通过生物信息学分析和构象分析，确定了突变体的致病机制。以下八种突变（六个新的和两个已知的）在六个基因中的八个家庭：WNT10A [c.742C > T（p.R248*）]、LRP6 [c.1518G > A（p.W506*），c.2791 + 1G > T]，AXIN2 [c.133_134insGCCAGG（p.44_45insGQ）]、PAX9 [c.439C > T（p.Q147*）、c.453_454insCCAGC（p.L154QfsTer60）]、MSX1 [c.603_604del（p.A203GfsTer10）]和PITX2 [c.522C > G（p.Y174*）]。生物信息学和构象分析表明，这些突变体的蛋白质结构发生了严重的改变，并表明这些结构异常可能会导致功能障碍。我们的研究扩展了非综合征型TA患者的突变谱，并为遗传咨询提供了有价值的数据。TA在具有未知病因变异的患者/家庭中的发病机制需要进一步探讨。外显子组测序和桑格测序显示，在43个非综合征性牙齿发育不全家系的72例患者中，19%（8/43）的患者存在已知致病基因的变异。本研究扩展了非综合征型TA患者的突变谱，为遗传咨询提供了有价值的数据。
Tooth agenesis (TA) is a congenital abnormality that may present as syndromic or nonsyndromic. Considering its complex genetic aetiology, the aim of this study was to uncover the pathogenic mutants in patients with nonsyndromic TA and analyse the characteristics of these mutants. Exome sequencing was performed to detect pathogenic variants in 72 patients from 43 unrelated families with nonsyndromic TA. All candidate variants were validated using Sanger sequencing. Bioinformatics and conformational analyses were performed to determine the pathogenic mechanisms of the mutants. The following eight mutations (six novel and two known) in six genes were identified in eight families: WNT10A [c.742C > T (p.R248*)], LRP6 [c.1518G > A (p.W506*), c.2791 + 1G > T], AXIN2 [c.133_134insGCCAGG (p.44_45insGQ)], PAX9 [c.439C > T (p.Q147*), c.453_454insCCAGC (p.L154QfsTer60)], MSX1 [c.603_604del (p.A203GfsTer10)] and PITX2 [c.522C > G (p.Y174*)]. Bioinformatics and conformational analyses showed that the protein structures were severely altered in these mutants, and indicated that these structural abnormalities may cause functional disabilities. Our study extends the mutation spectrum in patients with nonsyndromic TA and provides valuable data for genetic counselling. The pathogenic mechanisms of TA in patients/families with unknown causative variants need to be explored further. Exome sequencing and Sanger sequencing revealed variations in known pathogenic genes in 19% (8/43) of 72 patients from 43 unrelated families with nonsyndromic tooth agenesis. This study extends the mutation spectrum in patients with nonsyndromic TA and provides valuable data for genetic counselling.
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