目的·探索先天缺牙相关的外异蛋白A受体（ectodysplasin A receptor，EDAR）基因突变位点，初步分析EDAR基因突变导致综合征型和非综合征型缺牙的原因。方法·研究对象为就诊于上海交通大学医学院附属第九人民医院口腔第二门诊部的先天缺牙患者及其家系成员，提取其外周血中的基因组DNA进行全外显子组测序。通过初步筛选后，用PolyPhen-2、Mutation Taster、Provean对潜在突变位点的有害性进行预测，对分析后的突变位点进行Sanger测序验证。进行突变位点的保守性分析，使用在线工具Swiss-Model进行同源建模，分析EDAR蛋白的三维结构变化。对患者及其家系成员的先天缺牙和全身发育情况进行临床检查。结果·在纳入的先天缺牙患者中共发现5名EDAR基因突变患者，1名患者携带移码突变c.368_369insC（p.L123fs），4名患者携带错义突变。在EDAR错义突变患者中，有2名患有非综合征型缺牙（non-syndromic tooth agenesis，NSTA），分别携带c.77C>A（p.A26E）纯合突变和c.380C>T（p.P127L）杂合突变。另外2名患有少汗型外胚层发育不良（hypohidrotic ectodermal dysplasia，HED），均带有2个基因突变位点：1名为EDAR复合杂合患者，携带来自父亲的EDAR c.77C>T（p.A26V）和来自母亲的EDAR c.1281G>C（p.L427F）；另1名为EDAR、外异蛋白A（ectodysplasin A，EDA）双基因突变患者，EDAR c.1138A>C（p.S380R）和EDA c.1013C>T（p.T338M）均来自母亲，这2个位点在此前的报道中仅与NSTA相关。EDAR c.1281G>C（p.L427F）、c.77C>A（p.A26E）为未被报道过的错义突变新位点。错义突变可能通过改变氨基酸残基极性、电荷或体积等，对蛋白空间构象造成影响；移码突变造成了非3整倍数的碱基增加，可能导致蛋白的截短或降解。结论·发现了2个新的EDAR错义突变位点，报道了由EDAR纯合突变导致的NSTA以及由EDA、EDAR双基因突变导致HED的病例，扩展了对于EDAR突变造成HED和NSTA的致病机制的理解。

Objective ·To explore EDAR (ectodysplasin A receptor) gene variants that lead to congenital tooth agenesis, and preliminarily analyze the reasons why variants in EDAR can cause both syndromic and non-syndromic tooth agenesis. Methods ·Patients with congenital tooth agenesis admitted to the Department of 2nd Dental Center, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine and their family members were included, and genomic DNA from their peripheral blood was extracted for whole exome sequencing (WES). After preliminary screening, PolyPhen-2, Mutation Taster, and Provean were used to predict the harmfulness of potential variants. The screened variants in patients and their families were verified by Sanger sequencing. Conservation analysis of variants was performed, and Swiss-Model was used to analyze the changes in the three-dimensional structure of EDAR. The teeth and syndromic phenotype of the patients and their family members were investigated. Results ·Among the included congenital tooth agenesis patients, five patients with EDAR mutations were found, one with EDAR frameshift mutation c.368_369insC(p.L123fs) and the other four with EDAR missense mutations. Two of these four patients were diagnosed as non-syndromic tooth agenesis (NSTA), resulted from c.77C>A(p.A26E) homozygous mutation and c.380C>T(p.P127L) heterozygous mutation, respectively. The other two patients with two variants were diagnosed as hypohidrotic ectodermal dysplasia (HED). One compound heterozygous missense mutation patient carried EDAR c.77C>T(p.A26V) from her father and EDAR c.1281G>C (p.L427F) from her mother; the other patient with both EDAR and EDA mutations carried EDAR c.1138A>C(p.S380R) heterozygous mutation and EDA c.1013C>T(p.T338M) hemizygous mutation. Both variants were from his mother and were reported to be related with NSTA. Two of these missense mutations, EDAR c.1281G>C(p.L427F) and EDAR c.77C>A (p.A26E), had not been reported before. The missense mutations affected the protein's spatial conformation by altering the polarity, charge, or volume of the amino acid residues. The frameshift mutation caused a non-triplet base addition, which probably led to protein truncation or degradation. Conclusion ·Two new EDAR missense mutations are discovered. An NSTA patients with EDAR homozygous mutations and an HED patient with both EDA and EDAR mutations are reported. It expands the understanding of pathogenic mechanisms of EDAR mutations causing HED and NSTA.