WNT10A mutations account for ¼ of population‐based isolated oligodontia and show phenotypic correlations

Abstract

A large proportion (>50%) of patients with isolated oligodontia were recently reported with WNT10A mutations. We have analyzed a population-based cohort of 102 individuals diagnosed with non-syndromic oligodontia and a mean of 8.2 missing teeth. The cohort included 94 families and screening of WNT10A identified that 26 probands (27.7%) had at least one WNT10A variant. When we included the MSX1, PAX9, AXIN2, EDA, EDAR, and EDARADD genes, 38.3% of probands were positive for a mutation. Biallelic WNT10A mutations were strongly associated with a larger number of missing teeth (11.09) when compared to both monoallelic WNT10 mutations (6.82) and the group without mutations in WNT10A, MSX1, PAX9, AXIN2, EDA, EDAR, or EDARADD (7.77). Genotype-phenotype analysis of individuals with WNT10A mutations showed that premolars were the most common missing teeth. Furthermore, biallelic WNT10A mutations were associated with absence of maxillary and mandibular molars as well as mandibular central incisors. Maxillary central incisors were always present. Thus, our study indicates that WNT10A mutations are associated with both the type and numbers of missing teeth. Furthermore, we show that this population-based cohort of isolated oligodontia had a considerably lower frequency of mutated WNT10A alleles and a lower mean number of missing teeth when compared to patients recruited from dental specialist centers.

Abnormal primary and permanent dentitions with ectodermal symptoms predict WNT10A deficiency

“…None of the patients presented with the typical phenotype of EDA - or EDAR -induced hypohidrotic ED [24, 25] and the ectodermal signs and symptoms were incongruous with any defined ED-entity. The spectrum of ectodermal symptoms among our seven patients is consistent with that previously reported in patients with bi-allelic WNT10A mutations [3–6, 8, 10], and even in some patients with mono-allelic mutations [4, 6, 8, 11, 12]. Notably, with the exception of tooth agenesis, the signs and symptoms from ectodermal appendages in a majority of individuals in our cohort were subtle and in several cases even not experienced as abnormal by the study persons or their parents.…”

“…Genetic analysis of exons and their flanking sequences of WNT10A was performed as described previously [11], and the results revealed bi-allelic mutations in all seven individuals. All parents were found to be heterozygous.…”

“…Studies of patients with non-syndromic oligodontia (agenesis of 6–28 teeth) referred for centralized treatments revealed a carrier frequency of up to 56% for WNT10A mutations [8]. However, a population-based study of Swedish individuals with isolated oligodontia revealed that the frequency of at least one WNT10A mutation in non-related probands was 28% [11]. When adding mutations in the genes MSX1, PAX9, AXIN2, EDA, EDAR, and EDARADD in the same material the frequency of genetically verified isolated oligodontia reached 38.3%.…”

“…Bi-allelic WNT10A mutations are usually associated with a larger number of missing teeth when compared to mono-allelic mutations [3, 4, 6, 8–11, 14]. Noteworthy, the penetrance among heterozygotes is incomplete and a considerable proportion of carriers do not express any tooth anomalies at all [12].…”

Mutations in WNT10B Are Identified in Individuals with Oligodontia

“…Genotype-phenotype analysis of individuals with WNT10A mutations by our previous study and others revealed that premolars were the most commonly missing teeth (62.5%-68.8%), whereas incisors were missing only 18.8%-31.3% of the time. 8,31,32 In contrast, the most frequently missing permanent teeth in the affected individuals with WNT10B variants were the lateral incisors (83.3%; Table 1), whereas premolars were missing only 51.4% of the time, a pattern clearly different from the oligodontia patterns resulting from WNT10A mutations. Given that the most commonly affected teeth in DPSCs were isolated and cultured as described in our previous study.…”