WNT10A双等位基因突变导致非综合征型先天缺牙1例的遗传学分析及文献复习  

Genetic analysis and literature review of a case of non-syndromic tooth agenesis caused by compound heterozygous mutations in WNT10A

作　　者：丁婷婷 刘浩辰 DING Tingting;LIU Haochen(Department of Stomatology,Beijing Children's Hospital,Capital Medical University,National Center for Children's Health,Beijing 100045,China;Department of Prosthodontics,Peking University School and Hospital of Stomatology&National Center for Stomatology&National Clinical Research Center for Oral Diseases&National Engineering Research Center of Oral Biomaterials and Digital Medical Devices&Central Laboratory,Beijing 100081,China)

机构地区：[1]国家儿童医学中心/首都医科大学附属北京儿童医院口腔科,北京100045 [2]北京大学口腔医学院·口腔医院/国家口腔医学中心/国家口腔疾病临床医学研究中心/口腔生物材料和数字诊疗装备国家工程研究中心修复科,北京100081

出　　处：《山东大学学报(医学版)》2025年第3期92-98,116,共8页Journal of Shandong University:Health Sciences

基　　金：国家自然科学基金(81600851)。

摘　　要：目的探讨1例非综合征型先天缺牙患者的致病基因突变情况,并对其牙齿缺失特点进行研究分析。方法收集患者家系及正常对照的血液样本并提取DNA。通过外显子测序及Sanger测序来发现并验证致病基因突变。使用预测软件Polyphen-2、Mutation Taster、CADD及fathmm来分析突变对功能的影响。使用保守性分析及蛋白质三维结构分析来预测突变对蛋白质功能的影响。检索以往发表文献,分析突变基因相关的缺牙表型。结果在1例非综合征先天缺牙患者中发现了罕见的WNT10A双等位基因突变(c.637G>A/p.Gly213Ser和c.1009G>T/p.Val337Phe),其中c.1009G>T突变是新突变。Polyphen-2、CADD及fathmm预测这两个突变是有害的;Mutation Taster预测c.637G>A突变是良性的,预测c.1009G>T突变是有害的。保守性分析显示这两个突变位点(213Gly和337Val)位于进化过程中高度保守区域,蛋白质三维结构分析显示氨基酸改变(p.Gly213Ser和p.Val337Phe)对蛋白质功能造成了影响。总结142例WNT10A突变导致的非综合征型先天缺牙患者资料,发现患者缺牙情况左右对称。最容易缺失的牙齿位置依次为下颌第二前磨牙(60.2%)、上颌第二前磨牙(58.5%)和上颌侧切牙(53.9%);最不容易缺失的牙齿依次为上颌中切牙(2.1%)、下颌第一磨牙(12.0%)和上颌第一磨牙(12.3%)。结论本研究在中国人群中的1例非综合征型先天缺牙患者中鉴定出WNT10A双等位基因突变(c.637G>A/p.Gly213Ser和c.1009G>T/p.Val337Phe),其中c.1009G>T(p.Val337Phe)为首次报道的变异,扩大了WTN10A基因突变谱。另外,我们进行了WNT10A相关的非综合征型先天缺牙表型分析,为临床诊断、治疗和遗传咨询提供借鉴参考。Objective To investigate the pathogenic gene mutations in a patient with non-syndromic tooth agenesis(NSTA)and analyze the characteristics of tooth absence.Methods Blood samples were collected from the patient's family and normal controls,and DNA was extracted.Whole exon sequencing(WES)and Sanger sequencing were used to identify and verify the pathogenic gene mutations.Functional impacts of the mutations were analyzed using the prediction software Polyphen-2,Mutation Taster,CADD,and fathmm.Conservation analysis and protein three-dimensional structure analysis were used to predict the effects of the mutations on protein function.Previously published literature was reviewed to analyze the tooth agenesis phenotypes associated with the mutated gene.Results Rare compound heterozygous mutations in WNT10A(c.637G>A/p.Gly213Ser and c.1009G>T/p.Val337Phe)in a patient with NSTA were identified,with the c.1009G>T mutation being novel.Polyphen-2,CADD,and fathmm predicted both mutations to be deleterious;Mutation Taster predicted c.637G>A to be benign and c.1009G>T to be deleterious.Conservation analysis showed that both mutation sites(213Gly and 337Val)were highly conserved through evolution,and three-dimensional structure analysis of the proteins indicated that the amino acid changes(p.Gly213Ser and p.Val337Phe)affected protein function.142 cases of NSTA caused by WNT10A mutations were reviewed,and it is found that tooth loss was bilaterally symmetrical.The most frequently missing tooth positions were the mandibular second premolar(60.2%),maxillary second premolar(58.5%),and maxillary lateral incisor(53.9%);the least frequently missing tooth positions were the maxillary central incisor(2.1%),mandibular first molar(12.0%),and maxillary first molar(12.3%).Conclusion This study identified compound heterozygous mutations in WNT10A(c.637G>A/p.Gly213Ser and c.1009G>T/p.Val337Phe)in a Chinese patient with NSTA,with the c.1009G>T(p.Val3337Phe)variant being reported for the first time,thus expanding the mutation spectrum of the WNT10

关 键 词：非综合征型先天缺牙 基因突变 WNT10A 基因型表型分析 遗传咨询 

分 类 号：R574[医药卫生—消化系统]