Whole-Exome Sequencing in Patients with Tooth Agenesis and Neurodevelopmental Disorders: A Descriptive Case Series

Tooth agenesis (TA) is a common developmental abnormality that may occur as an isolated trait or as part of a multisystem disorder. Its genetic architecture remains incompletely characterized, particularly in individuals with neurodevelopmental disorders (NDDs). This descriptive case series aimed to investigate potentially relevant genetic variants in a clinically selected cohort of patients with TA using whole-exome sequencing (WES). Ten patients with TA and neurological or neurodevelopmental conditions were recruited at the IRCCS Oasi Research Institute of Troina between January 2024 and July 2026. The cohort included eight males and two females (age range: 5-50 years). The associated clinical spectrum included autism spectrum disorder (ASD), intellectual disability (ID), language impairment, behavioral abnormalities, and Down syndrome (DS). WES was performed in the examined cohort and variants were prioritized according to population frequency, predicted functional impact, inheritance pattern, and phenotypic concordance. The cohort comprised nine patients with hypodontia and one with oligodontia. Thirty variants involving 28 genes were identified. A homozygous GLI3 p.Gly727Arg variant, inherited from two heterozygous parents, was detected in an eight-year-old boy with ASD, global developmental delay, and hypodontia. Pathogenic or likely pathogenic loss-of-function variants in BCL11B were identified in two girls with ID and hypodontia. A likely pathogenic NIPBL splice-site variant was identified in a 15-year-old boy with hypodontia. His similarly affected father carried a novel FGFR1 p.Asn185His variant that was absent in the son, excluding it as the sole explanation for the familial dental phenotype. A 50-year-old man with DS and oligodontia carried the recurrent pathogenic BBS1 p.Met390Arg allele in the heterozygous state, together with variants of uncertain significance in PTH1R and STAT3. However, none of these variants independently explained his dental phenotype. The remaining variants were primarily relevant to the associated neurological phenotypes or represented secondary findings. This descriptive case series illustrates the clinical and genetic heterogeneity of TA in individuals with NDDs. Although the findings do not establish causal relationships with TA, they highlight the importance of distinguishing the general clinical significance of a variant from its specific relevance to dental development. Replication in larger cohorts and functional validation will be required to clarify the contribution of the identified candidate variants.