Oculoskeletodental syndrome: expansion and review of the clinical and molecular phenotype

Introduction Oculoskeletodental syndrome (OCSKD) is a rare ciliopathy characterized by dysmorphic facial features, congenital cataracts, dental and skeletal anomalies, developmental delays, and strokes. PIK3C2A plays a crucial role in membrane trafficking and various intracellular signaling pathways by synthesizing lipid messengers. To date, only two studies describing four families have linked PIK3C2A loss-of-function variants to OCSKD, with limited functional analyses in primary cell lines. Methods Patient selection, clinical phenotype reporting, and sample collection were conducted after obtaining written informed consent. Exome sequencing was performed to identify genetic variants potentially causative of the disease, and Sanger sequencing was used for segregation analysis. Functional studies were performed using primary cell lines from patients to characterize the identified candidate genetic variants. Results Here, we report an additional affected individual from a consanguineous family who presented with a similar expanded phenotype. Exome sequencing identified a novel homozygous nonsense variant of PIK3C2A (NM_002645.4: c.2177C>G: p. Ser726*). Functional analysis of the primary cell lines derived from the patient confirmed PIK3C2A protein knockout. Conclusion Our findings provide a detailed clinical description, further expanding the phenotypic spectrum associated with this condition. We also provide a review of subjects’ phenotypes reported to date with this condition.