Critical Considerations in Calling Disease-Causing Mutations in Nonsyndromic Oligodontia.

Oligodontia, the absence of six or more teeth excluding third molars, is a rare genetic condition, unlike hypodontia (missing one or more teeth), which is a relatively common human disease. To identify the genetic etiology of nonsyndromic oligodontia (NSO) families, we performed mutational analysis and investigated the functional effects of identified mutations. Whole-exome sequencing was conducted on recruited families with NSO. Bioinformatic analysis identified mutations in oligodontia-causing candidate genes, which were confirmed by Sanger sequencing and segregation within families. The impact of mutations on the EDA signaling pathway was assessed using luciferase activity analysis. mutations were identified in three NSO families. A homozygous missense mutation (NM_022336.4: c.319A>G p.(Met107Val)) was found in the singleton proband of family 1. The proband of family 2 carried compound heterozygous mutations: a maternal missense mutation (c.319A>G p.(Met107Val)) and a paternal missense variant (c.1270G>A p.(Val424Met)). The proband of family 3 had heterozygous mutations: a maternal missense mutation (c.389T>A p.(Ile130Asn)) and paternal intronic variants in cis (c.[357-4G>A;440+50C>T]). Luciferase assays confirmed reduced transcriptional activity for all identified missense mutations, while splicing assays revealed altered splicing patterns. In conclusion, recessive mutations, including novel ones, were identified in NSO families, and their pathological mechanism was explored through transcriptional activity measurements.