Dose Dependence Effect in Biallelic WNT10A Variant-Associated Tooth Agenesis Phenotype.
Dose Dependence Effect in Biallelic WNT10A Variant-Associated Tooth Agenesis Phenotype.
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DOI：
10.3390/diagnostics12123087
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发表时间：
2022-12-07
期刊：
影响因子：
3.6
通讯作者：
Han, Dong
中科院分区：
文献类型：
--
作者：
Liu, Haochen;Lin, Bichen;Liu, Hangbo;Su, Lanxin;Feng, Hailan;Liu, Yang;Yu, Miao;Han, Dong
关键词：
本研究的目的是确定齿甲甲真皮发育不良综合征 (OODD) 或非综合征性牙齿发育不全患者的致病基因变异。招募了四名没有血缘关系的牙齿发育不全者及其可用的家庭成员。从四名先证者和五名家庭成员身上采集外周血。全外显子组测序（WES）和桑格测序用于鉴定致病基因变异。生物信息学预测了这些变异的危害性。我们在四名患者中鉴定出了 WNT10A 基因的四种双等位基因变异，分别为：先证者#660：c.1176C > A (p.Cys392*) 和 c.812G > A (p.Cys271Tyr)；先证者#681：c.637G > A (p.Gly213Ser) 和 c.985C > T (p.Arg329*)；先证者#829：c.511C > T (p.Arg171Cys) 和 c.637G > A (p.Gly213Ser)；先证者#338：c.926A> G (p.Gln309Arg) 和 c.511C > T (p.Arg171Cys)。其中，有两个变体（c.812G > A；p.Cys271Tyr 和 c.985C > T；p.Arg329*）此前未曾报道。生物信息学分析表明，这6个变异体的致病性存在差异。三级结构分析表明，这些变体预计会对 WNT10A 蛋白造成结构损伤。基因型-表型分析表明，具有更多有害影响的双等位基因变异，例如无义变异，会导致OODD综合征（#660 Ⅱ-1）或严重非综合征性牙齿发育不全（NSTA）（#681 Ⅱ-1）；有害影响较小的双等位变体，例如错义变体，会引起轻度形式的 NSTA（#829 Ⅱ-2 和 #338 Ⅱ-1）。具有杂合变异的个体呈现出轻度形式的 NSTA 或正常状态。我们的结果进一步表明WNT10A致病性对牙齿发育不全模式存在剂量依赖性，这拓宽了WNT10A的变异谱和表型谱，有助于临床诊断、治疗和遗传咨询。
The goal of this study was to identify the pathogenic gene variants in patients with odonto-onycho-dermal dysplasia syndrome (OODD) or nonsyndromic tooth agenesis. Four unrelated individuals with tooth agenesis and their available family members were recruited. Peripheral blood was collected from four probands and five family members. Whole-exome sequencing (WES) and Sanger sequencing were used to identify the pathogenic gene variants. The harmfulness of these variations was predicted by bioinformatics. We identified four biallelic variants of the WNT10A gene in four patients, respectively: the proband#660: c.1176C > A (p.Cys392*) and c.812G > A (p.Cys271Tyr); the proband#681: c.637G > A (p.Gly213Ser) and c.985C > T (p.Arg329*); the proband#829: c.511C > T (p.Arg171Cys) and c.637G > A (p.Gly213Ser); and the proband#338: c.926A> G (p.Gln309Arg) and c.511C > T (p.Arg171Cys). Among them, two variants (c.812G > A; p.Cys271Tyr and c.985C > T; p.Arg329*) were previously unreported. Bioinformatics analysis showed that the pathogenicity of these six variants was different. Tertiary structure analysis showed that these variants were predicted to cause structural damage to the WNT10A protein. Genotype–phenotype analysis showed that the biallelic variants with more harmful effects, such as nonsense variants, caused OODD syndrome (#660 Ⅱ-1) or severe nonsyndromic tooth agenesis (NSTA) (#681 Ⅱ-1); the biallelic variants with less harmful effects, such as missense variants, caused a mild form of NSTA (#829 Ⅱ-2 and #338 Ⅱ-1). Individuals with a heterozygous variant presented a mild form of NSTA or a normal state. Our results further suggest the existence of the dose dependence of WNT10A pathogenicity on the tooth agenesis pattern, which broadens the variation spectrum and phenotype spectrum of WNT10A and could help with clinical diagnosis, treatment, and genetic counseling.
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