Synergistic Mutations of and in Familial Tooth Agenesis.

Familial tooth agenesis (FTA), distinguished by developmental failure of selected teeth, is one of the most prevalent craniofacial anomalies in humans. Mutations in genes involved in WNT/β-catenin signaling, including  , , , and are known to cause FTA. However, mutational interactions among these genes have not been fully explored. In this study, we characterized four FTA kindreds with pathogenic mutations: p.(Gln1252*), p.(Met168Arg), p.(Ala754Pro), and p.(Asn1075Ser). The three missense mutations were predicted to cause structural destabilization of the LRP6 protein. Two probands carrying both an mutant allele and a variant exhibited more severe phenotypes, suggesting mutational synergism or digenic inheritance. Biallelic mutations in a patient with many missing teeth further supported the dose-dependence of -associated FTA. Analysis of 21 FTA cases with 15 different loss-of-function mutations revealed high heterogeneity of disease severity and a distinctive pattern of missing teeth, with maxillary canines being frequently affected. We hypothesized that various combinations of sequence variants in WNT-related genes can modulate WNT signaling activities during tooth development and cause a wide spectrum of tooth agenesis severity, which highlights the importance of exome/genome analysis for the genetic diagnosis of FTA in this era of precision medicine.