Familial Tooth Agenesis in Lebanese Patients: Clinical Characterization and Whole-Exome Identification of Rare...

Tooth agenesis (TA) is a common developmental anomaly of the dentition with marked phenotypic and genetic heterogeneity, yet data from Middle Eastern families are limited. The aims of this study were twofold: first, to describe the clinical features and inheritance patterns of familial TA in Lebanese kindreds and to investigate rare segregating exonic variants that may contribute to these phenotypes; and second, to provide a clinic‑based estimate of TA prevalence and patterns in the same population context.

Records of 157 consecutive patients attending an orthodontic and pediatric dental clinic in Akkar, Lebanon (2015-2019), were reviewed for TA, excluding third molars, to obtain a descriptive, clinic‑based prevalence estimate. In parallel, from a larger craniomaxillofacial cohort, two multigenerational families with TA across at least two generations were recruited. Detailed clinical and radiographic assessments were performed. Whole‑exome sequencing (WES) was undertaken in five affected individuals. Variants were filtered by population frequency, predicted functional impact, and segregation, and conservation was assessed by multispecies protein sequence alignment.

TA was identified in 13.1% of clinic patients (95% confidence interval (CI) 8.4-17.8%). In family 1, six individuals had familial TA without a confirmed syndromic diagnosis, and WES revealed a heterozygous triple functional domain protein (TRIO) missense variant c.8312C>T (p.Ser2771Leu) in exon 53 that co‑segregated with TA in sequenced members. In family 2, five relatives with TA carried a heterozygous calcium voltage‑gated channel auxiliary subunit alpha2delta 2 (CACNA2D2) missense variant c.284G>A (p.Arg95His) in exon 2, which, likewise, co‑segregated with the phenotype in sequenced members. Ser2771 in TRIO and Arg95 in CACNA2D2 lie in highly conserved regions within the immunoglobulin‑like I‑set domain and adjacent to the von Willebrand factor A (VWA) domain, respectively. The TRIO change was absent from the Genome Aggregation Database (gnomAD), whereas the CACNA2D2 variant corresponded to rs149979955, a very rare allele previously annotated as likely benign.

This clinic‑based cohort provides a local descriptive epidemiologic context for TA, and the two Lebanese families broaden the clinical and putative genetic spectrum of familial TA. The rare segregating variants identified in TRIO and CACNA2D2 support these genes as candidate contributors to familial TA without a confirmed syndromic diagnosis; however, additional functional and genetic studies are needed before they can be considered for routine diagnostic use.