Salvi Alessandro, Giacopuzzi Edoardo, Bardellini Elena, Amadori Francesca, Ferrari Lia, De Petro Giuseppina, Borsani Giuseppe, Majorana Alessandra
Department of Molecular and Translational Medicine, Division of Biology and Genetics, University of Brescia, I-25123 Brescia, Italy.
Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, Dental Clinic, University of Brescia, I-25123 Brescia, Italy.
Int J Mol Med. 2016 Nov;38(5):1338-1348. doi: 10.3892/ijmm.2016.2742. Epub 2016 Sep 19.
Dental agenesis is one of the most common congenital craniofacial abnormalities. Dental agenesis can be classified, relative to the number of missing teeth (excluding third molars), as hypodontia (1 to 5 missing teeth), oligodontia (6 or more missing teeth), or anodontia (lack of all teeth). Tooth agenesis may occur either in association with genetic syndromes, based on the presence of other inherited abnormalities, or as a non-syndromic trait, with both familiar and sporadic cases reported. In this study, we enrolled 16 individuals affected by tooth agenesis, prevalently hypodontia, and we carried out direct Sanger sequencing of paired box 9 (PAX9) and Msh homeobox 1 (MSX1) genes in 9 subjects. Since no mutations were identified, we performed whole exome sequencing (WES) in the members of 5 families to identify causative gene mutations either novel or previously described. Three individuals carried a known homozygous disease mutation in the Wnt family member 10A (WNT10A) gene (rs121908120). Interestingly, two of these individuals were siblings and also carried a heterozygous functional variant in EDAR-associated death domain (EDARADD) (rs114632254), another disease causing gene, generating a combination of genetic variants never described until now. The analysis of exome sequencing data in the members of other 3 families highlighted new candidate genes potentially involved in tooth agenesis and considered suitable for future studies. Overall, our study confirmed the major role played by WNT10A in tooth agenesis and the genetic heterogeneity of this disease. Moreover, as more genes are shown to be involved in tooth agenesis, WES analysis may be an effective approach to search for genetic variants in familiar or sporadic tooth agenesis, at least in more severe clinical manifestations.
牙齿发育不全是最常见的先天性颅面畸形之一。根据缺失牙齿的数量（不包括第三磨牙），牙齿发育不全可分为少牙症（缺失1至5颗牙齿）、无牙症（缺失6颗或更多牙齿）或无牙畸形（所有牙齿均缺失）。牙齿发育不全可能与遗传综合征相关，基于其他遗传异常的存在，也可能作为一种非综合征性特征出现，既有家族性病例也有散发性病例报道。在本研究中，我们招募了16名受牙齿发育不全影响的个体，主要是少牙症患者，并对9名受试者的配对盒9（PAX9）和Msh同源盒1（MSX1）基因进行了直接桑格测序。由于未发现突变，我们对5个家庭的成员进行了全外显子组测序（WES），以鉴定新的或先前描述的致病基因突变。三名个体在Wnt家族成员10A（WNT10A）基因（rs121908120）中携带已知的纯合疾病突变。有趣的是，其中两名个体是兄弟姐妹，并且在另一个致病基因EDAR相关死亡结构域（EDARADD）（rs114632254）中也携带杂合功能变异，产生了迄今为止从未描述过的遗传变异组合。对其他3个家庭成员的外显子组测序数据分析突出了可能参与牙齿发育不全且适合未来研究的新候选基因。总体而言，我们的研究证实了WNT10A在牙齿发育不全中的主要作用以及该疾病的遗传异质性。此外，随着越来越多的基因被证明与牙齿发育不全有关，WES分析可能是在家族性或散发性牙齿发育不全中寻找遗传变异的有效方法，至少在更严重的临床表现中如此。
