Comparative analysis of rare EDAR mutations and tooth agenesis pattern in EDAR‐ and EDA‐associated nonsyndromic oligodontia
Comparative analysis of rare EDAR mutations and tooth agenesis pattern in EDAR‐ and EDA‐associated nonsyndromic oligodontia
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DOI：
10.1002/humu.24104
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发表时间：
2020-09
期刊：
影响因子：
3.9
通讯作者：
Liutao Zhang;Miao Yu;Sing-Wai Wong;H. Qu;T. Cai;Yang Liu;Hao-chen Liu;Z. Fan;Jinglei Zheng;Yongsheng Zhou;H. Feng;D. Han
中科院分区：
文献类型：
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作者：
Liutao Zhang;Miao Yu;Sing-Wai Wong;H. Qu;T. Cai;Yang Liu;Hao-chen Liu;Z. Fan;Jinglei Zheng;Yongsheng Zhou;H. Feng;D. Han
非综合征性少牙是一种罕见的先天畸形。外胚珠蛋白A受体(EDAR)基因突变是少汗性外胚层发育不良的主要原因，但在非综合征性少牙症中很少有报道。这项研究调查了多发性非综合征性少牙的EDAR突变，并比较分析了EDAR和EDA相关的牙齿发育不全模式。采用全外显子组测序和家系分离进行突变筛查。用进化保守性和构象分析来评估EDAR突变体的潜在致病影响。在非综合征性少牙病例中，有10.7%的病例存在EDAR突变。我们报道了7个EDAR杂合突变，包括5个新突变(c.404G>；A、c.871G>；A、c.43G>；A、c.1072C>；T和c.1109T>；C)和两个已知突变(c.319A>；G和c.1138A>；C)。基因-表型相关分析表明，EDAR相关的牙齿发育不全模式与EDA明显不同。在EDAR基因突变患者中，下颌第二前磨牙缺失最多(57.69%)。我们的结果为非综合征性牙缺失的基因分型研究提供了新的证据，并提示EDAR单倍体不足导致非综合征性牙齿发育不全。此外，EDAR和EDA相关的牙齿发育不全之间的明显模式可以作为这种遗传病的临床遗传学诊断中的突变筛查的指南。
Nonsyndromic oligodontia is a rare congenital anomaly. Mutations in the ectodysplasin A receptor (EDAR) gene are the primary cause of hypohidrotic ectodermal dysplasia but are rarely reported in nonsyndromic oligodontia. This study investigated EDAR mutations in multiplex nonsyndromic oligodontia and comparatively analyzed the EDAR‐ and EDA‐related tooth agenesis patterns. Mutation screening was carried out using whole‐exome sequencing and familial segregation. Evolutionary conservation and conformational analyses were used to evaluate the potential pathogenic influence of EDAR mutants. EDAR mutations were found to occur in 10.7% of nonsyndromic oligodontia cases. We reported seven heterozygous mutations of EDAR, including five novel mutations (c.404G>A, c.871G>A, c.43G>A, c.1072C>T, and c.1109T>C) and two known mutations (c.319A>G and c.1138A>C). Genotype–phenotype correlation analysis demonstrated that the EDAR‐related tooth agenesis pattern was markedly different from EDA. The mandibular second premolars were most frequently missing (57.69%) in EDAR‐mutated patients. Our results provide new evidence for the genotypic study of nonsyndromic oligodontia and suggest that EDAR haploinsufficiency results in nonsyndromic tooth agenesis. Furthermore, the distinct pattern between EDAR‐ and EDA‐related tooth agenesis can be used as a guide for mutation screening during the clinical genetic diagnosis of this genetic disorder.