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.

Figure 1. Panoramic radiographs of dentitions with tooth agenesis.

Congenitally missing teeth are denoted with asterisks (*), and peg-shaped maxillary lateral incisors with arrows. All radiographs show many retained deciduous teeth. A. Dentition of a 15-year-old girl (family 219) with a heterozygous frameshift mutation K237SfsX2 in MSX1. All second premolars and third molars, maxillary first premolars and mandibular central incisors are missing. Maxillary lateral incisors are peg-shaped. B. 11-year-old girl (family 283) with a heterozygous missense mutation p. R47P in PAX9 lacks all third molars, two maxillary second molars, three second premolars and mandibular central incisors. Left maxillary lateral incisor is peg-shaped. C. Severe tooth agenesis in a 13-year old boy (family 46) with a p.R357W mutation affecting the TNF domain of EDA. 10 permanent and 8 deciduous teeth, mostly in the anterior region, are missing. Maxillary left central incisor is conical. D. 19-year-old woman (family 266) lacks all third molars and lateral incisors, both maxillary canines, three second premolars and two deciduous lateral maxillary incisors. She was heterozygous for p.R325W in EDAR, p. S103F in EDARADD and p.G165R in WNT10A. E. Only 12 permanent teeth have developed in 27-year old woman (family 208) with a compound heterozygote mutations p.R113C and p.E194AfsX28 in WNT10A. Maxillary deciduous lateral incisors were also missing. F. 16-year old boy (family 261) with a heterozygous p.F228I variant in WNT10A lacks 13 permanent teeth including all third molars, mandibular second premolars, maxillary canines and five incisors.