Rare WDR19 Variants in Patients With Dental and Retinal Anomalies

Abstract

Genetic variants in WDR19 cause ciliopathies with craniofacial and ectodermal features, including dental and retinal anomalies. This study characterized the clinical and molecular features of patients with isolated dental anomalies harboring WDR19 variants. Clinical and radiographic evaluations and whole-exome sequencing were performed in 365 patients with dental and/or retinal anomalies. Immunohistochemical analysis of Wdr19 expression during mouse odontogenesis and structural modeling of mutant proteins were conducted. Five rare and three novel WDR19 variants were identified in 15 patients. Dental anomalies included tooth agenesis, mesiodens, and root maldevelopment. Autoimmune retinopathy was observed in two patients. Wdr19 was broadly expressed in developing tooth epithelium, Hertwig epithelial root sheath, retina, and epidermis. Structural modeling of WDR19 protein showed that the variants clustered within β-propeller and α-helical regions and were predicted to disrupt protein interactions or stability. The rarity of the identified variants, their localization within functionally important WDR19 domains, and their occurrence in multiple unrelated individuals with overlapping dental and retinal phenotypes support WDR19 as a candidate contributory gene. Wdr19 expression in odontogenic and retinal tissues, together with structural modeling predicting altered protein stability or interactions, further supports the biological plausibility of this association.