Candidate Gene Analysis of Tooth Agenesis Identifies Novel Mutations in Six Genes and Suggests Significant Role for WNT and EDA Signaling and Allele Combinations

Abstract

Failure to develop complete dentition, tooth agenesis, is a common developmental anomaly manifested most often as isolated but also as associated with many developmental syndromes. It typically affects third molars or one or few other permanent teeth but severe agenesis is also relatively prevalent. Here we report mutational analyses of seven candidate genes in a cohort of 127 probands with non-syndromic tooth agenesis. 82 lacked more than five permanent teeth excluding third molars, called as oligodontia. We identified 28 mutations, 17 of which were novel. Together with our previous reports, we have identified two mutations in MSX1, AXIN2 and EDARADD, five in PAX9, four in EDA and EDAR, and nine in WNT10A. They were observed in 58 probands (44%), with a mean number of missing teeth of 11.7 (range 4 to 34). Almost all of these probands had severe agenesis. Only few of the probands but several relatives with heterozygous genotypes of WNT10A or EDAR conformed to the common type of non-syndromic tooth agenesis, incisor-premolar hypodontia. Mutations in MSX1 and PAX9 affected predominantly posterior teeth, whereas both deciduous and permanent incisors were especially sensitive to mutations in EDA and EDAR. Many mutations in EDAR, EDARADD and WNT10A were present in several families. Biallelic or heterozygous genotypes of WNT10A were observed in 32 and hemizygous or heterozygous genotypes of EDA, EDAR or EDARADD in 22 probands. An EDARADD variant were in seven probands present together with variants in EDAR or WNT10A, suggesting combined phenotypic effects of alleles in distinct genes.

MSX1 mutations and associated disease phenotypes: genotype-phenotype relations

“…25 MSX1 and non-syndromic tooth agenesis Non-syndromic tooth agenesis (ns TA) is another common developmental anomaly that can be caused by MSX1 variants. 14 To date, nearly 20 MSX1 mutations have been related to ns TA 8,13,[26][27][28][29][30][31][32][33][34][35][36][37] (Table 2). Functional analyses of the mutant proteins suggest that haploinsufficiency of MSX1 underlies this phenotype.…”

Characterization of PAX9 variant P20L identified in a Japanese family with tooth agenesis

“…Since previous studies involving large numbers of subjects have found that the incidence of phenotypes attributable to PAX9 or MSX1 mutation is in the range of several percent [31,35], this was not unexpected. Those studies found a surprisingly high frequency of WNT10A mutation in patients with tooth agenesis.…”

“…(A) Locations of P20L and previously reported missense variants are shown with arrows above and below the PAX9 diagram, respectively [12,25–31]. Reported pathogenic variants with nonsense mutations or frameshifts are omitted.…”

The role of the dentist in the diagnosis of ectodermal dysplasia

“…The referral of the patient to a medical evaluation confirmed the diagnosis also based on the clinical findings, corroborating with authors who point out an essentially clinical diagnosis for ED 4,6,11 . Genetic mapping may also be used in order to identify the genes involved and the accurate location of the mutation, a piece of information of utmost importance in order to provide genetic counseling and also anticipate some medical care 25 . Genetic counseling contraindicates consanguineous marriages in order to prevent such X-linked disorders.…”

“…At clinical and radiographic examination, no missing teeth were found. The mother also presented few facial features, but the dental involvement was remarkable with 11,12,16,17,18,21,22,25,26,28,45,46,47,48,35, 36, 37, 38 missing teeth. The mother reported in the anamnesis that in adolescence she also had several missing teeth, which suggests that she also presented EDH.…”