The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, China.
Mol Genet Genomic Med. 2022 Oct;10(10):e2045. doi: 10.1002/mgg3.2045. Epub 2022 Aug 26.
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.
牙齿先天缺失（TA）是一种先天性异常，可能表现为综合征型或非综合征型。鉴于其复杂的遗传病因，本研究旨在发现非综合征型 TA 患者中的致病突变体，并分析这些突变体的特征。
对来自 43 个无关家系的 72 名非综合征型 TA 患者进行外显子组测序，以检测致病变异。使用 Sanger 测序验证所有候选变异。进行生物信息学和构象分析，以确定突变体的致病机制。
在 8 个家系中发现了 6 个新的和 2 个已知的突变（位于 6 个基因中）：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严重改变，并表明这些结构异常可能导致功能障碍。
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。需要进一步探索未知致病变异患者/家系中 TA 的发病机制。
