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Nonsyndromic hypodontia is a congenital absence of less than six permanent teeth, with a most common subtype maxillary lateral incisor agenesis (MLIA). Mutations in several genes have been described in severe tooth agenesis. The aim of this study was to search for the variants in wingless-type MMTV-integration site family member (WNT10A), paired box 9 (PAX9) and axis inhibitor 2 (AXIN2) genes, and investigate their potential role in the pathogenesis of non-syndromic hypodontia. Clinical examination and panoramic radiograph were performed in the cohort of 60 unrelated Slovak patients of Caucasian origin with nonsyndromic hypodontia including 37 MLIA cases and 48 healthy controls. Genomic DNA was isolated from buccal swabs and Sanger sequencing of WNT10A, PAX9 and AXIN2 was performed. Altogether, we identified 23 single-nucleotide variants, of which five were novel. We have found three rare nonsynonymous variants in WNT10A (p.Gly165Arg; p.Gly213Ser and p.Phe228Ile) in eight (13.33%) of 60 patients. Analysis showed potentially damaged WNT10A variant p.Phe228Ile predominantly occurred only in MLIA patients, and with a dominant form of tooth agenesis (odds ratio $$({\hbox {OR}}_{\mathrm{dom}}) = 9.841$$ ; $$P=0.045$$ ; 95% confidence interval (CI) 0.492–196.701; $${\hbox {OR}}_{\mathrm{rec}} = 0.773$$ ; $$P =1.000$$ ; 95% CI 0.015–39.877). In addition, the WNT10A variant p.Phe228Ile showed a trend associated with familial nonsyndromic hypodontia ( $$P =0.024$$ ; OR = 1.20; 95% CI 0.97–1.48). After Bonferroni correction, these effects remained with borderline tendencies. Using a 3D WNT10A protein model, we demonstrated that the variant Phe228Ile changes the protein secondary structure. In PAX9 and AXIN2, common variants were detected. Our findings suggest that the identified WNT10A variant p.Phe228Ile could represent risk for the inherited nonsyndromic hypodontia underlying MLIA. However, further study in different populations is required.

Selective tooth agenesis is the most common congenital disorder affecting the formation of dentition in humans. Both its forms (hypodontia and more severe oligodontia) can be found either in isolated form and they can be associated with systemic condition (syndromic tooth agenesis). In addition to previously known genes (PAX9, MSX1 and AXIN2) mutations in EDA, EDARADD and WNT10 gene were recently found to be involved in isolated forms of tooth agenesis. The objective of this study was to characterize the phenotype of affected members in two large families of Roma origin segregating severe isolated tooth agenesis with very variable phenotype and to perform mutation analysis of seven genes with aim to find causal mutation. 26 family members were clinically examined and coding regions of seven genes (MSX1, PAX9, AXIN2, EDA, EDAR, EDARADD and WNT10A) were sequenced. With exclusion of third molars, average number of missing teeth was 8.2 ? 4.9 in family 1 and 7.1 ? 2.3 in family 2. The most frequently missing teeth were maxillary lateral incisors and first premolars and mandibular central incisors. Sequencing revealed four potentially damaging variants (g.Ala40Gly in MSX1, g.Ala240Pro in PAX9, g.Pro50Ser in AXIN2 and g.Met9Ile in EDARADD); however, none of them was present in all affected family members. Variable phenotype in both families examined in this study is in favour of heterogeneous genetic cause of tooth agenesis in these families: possible interaction of several defected genes, sequence variants in regulatory regions and additional environmental factors is assumed.