1 | INTRODUCTION
Tooth agenesis is a pathological condition involving the absence of teeth due to a developmental failure(De Coster, Marks, Martens, & Huysseune, 2009). Non-syndromic (selective) tooth agenesis is one of the most common dental anomalies and is known to be associated with variants of MSX1 , PAX9 ,AXIN2 , EDA1 , EDAR , EDARADD ,WNT10A (Arte, Parmanen, Pirinen, Alaluusua, & Nieminen, 2013),WNT10B (P. Yu et al., 2016),LRP6 (Ockeloen et al., 2016; M. Yu, Wong, Han, & Cai, 2019) andGREM2 (Kantaputra et al., 2015). Of these, EDA , EDAR , EDARADD , and WNT10A are candidate genes of both non-syndromic tooth agenesis (NSTA) and syndromic tooth agenesis (STA). Ectodysplasin-A1 (EDA1) has been shown to bind specifically to the ectodysplasin-A receptor (EDAR), a member of the TNF receptor superfamily, and activate the nuclear factor kappa B (NF-κB) (Yan et al., 2000). The EDA-EDAR-NF-κB signaling pathway crosstalks to the WNT and BMP pathways(Shen et al., 2016) and plays an important role in embryonic ectodermal development(Cluzeau et al., 2011; Koppinen, Pispa, Laurikkala, Thesleff, & Mikkola, 2001).
Ectodermal dysplasia caused by EDAR mutations have been widely reported; according to M. Yu et al.(M. Yu et al., 2019) about 58 EDAR mutations have been found in STA. However, only seven mutations of EDAR have been found in patients with NSTA(Arte et al., 2013; Jonsson et al., 2018; Mumtaz, Nalbant, Blükba, Huma, & Malik, 2020; Zeng et al., 2017). Similarly,EDA1 is the only gene known to be associated with X-linked hypohidrotic ectodermal dysplasia (XLHED), which accounts for 95% of cases of hypohidrotic ectodermal dysplasia (HED). According to Trzeciak(Trzeciak & Koczorowski, 2016), there have been 345 reported cases of HED, of which 206 are due toEDA1 mutations. As at 2017, the Human Gene Mutation Database (HGMD Professional 2017.2) had registered 314 mutations in theEDA1 gene(Reyes-Reali et al., 2018).
In the present study, we investigate a novel missense mutation (EDAR c.338G>A p. Cys113Tyr), as well as three previously-reported missense mutations of EDA1 in Chinese Han families. The genotypes and phenotypes of all published EDARmutant patients and mutations at codon 289 of EDA1 in NSTA patients were analyzed. The aim of our study is to investigate the potentially pathogenic gene mutations for NSTA, to provide a genetic mechanism and a genotype-phenotype correlation for NSTA caused by mutations.