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. 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. 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. 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.

Oculoskeletodental syndrome (OCSKD) is a rare autosomal recessive ciliopathy caused by PIK3C2A loss-of-function variants, characterized by ocular, skeletal, and dental anomalies. Ocular findings most commonly include cataract and secondary glaucoma; however, high axial myopia and megalocornea have not been previously reported in the literature. We report a 2-year-old girl with OCSKD who presented with severe high axial myopia, bilateral megalocornea, lamellar cataracts, and developmental delay. Systemic evaluation revealed short stature and dental enamel hypoplasia. Clinical exome sequencing and whole mitochondrial genome sequencing identified a homozygous pathogenic variant in exon 8 PIK3C2A(NM_002645.4;ENST000000265970.11):c.1733_1736del(p.lle578LysfsTer3); NC_000011.10:g.17136594_17136597del [GRCh38]. The variant was classified as pathogenic and predicted to be damaging by MutationTaster2. Prenatal Sanger variant analysis testing of amniotic fluid in a fetus (to be the sibling of the index patient) showed the same variant in heterozygous form, confirming autosomal recessive inheritance. This case highlights phenotypic variability in PIK3C2A-related oculoskeletodental syndrome and raises the possibility of additional ocular involvement. Early molecular diagnosis enables accurate genetic counseling and supports targeted prenatal testing in affected families.

PIK3C2A is a member of the class II phosphatidylinositol-3-kinases (PI3K) family that catalyzes the phosphorylation of phosphatidylinositol (PI) into PI(3)P and of PI(4)P into PI(3,4)P2. These second messenger lipids regulate a wide range of downstream signaling pathways involved in many physiological functions and cellular processes, including cell proliferation, growth, survival, motility, and metabolism. PIK3C2A is also involved in the regulation of primary cilia formation and maintenance and in the regulation of receptor-mediated endocytosis at the base of the cilium. PIK3C2A was recently related to a novel oculoskeletodental syndrome (OCSKD MIM#618440), combining short stature, coarse facial features, ocular, and skeletal abnormalities. We describe here the fifth family presenting a PIK3C2A-related syndrome characterized by pulverulent cataracts and deafness. Using trio exome sequencing, we identified two novel compound heterozygous variants in PIK3C2A for which functional testing was necessary to assess the effect of one of the variants. Cellular studies of patient's-derived skin fibroblasts revealed a normal PIK3C2A protein level but a defective enzyme. Ciliary and cellular phenotype studies showed in the patient's cells impaired cilia formation and function as well as a reduced proliferative capacity. This study expands the clinical and mutational spectrum of PIK3C2A-related syndrome.

A pair of siblings was ascertained due to multiple congenital anomalies, including strikingly similar facial, skeletal, and ocular abnormalities. Exome sequencing of both the children and their mother revealed two novel PIK3C2A variants in the siblings, c.4381delC (p.Arg1461Glufs*31) and c.1555C > T (p.Arg519Ter). PIK3C2A belongs to the Class IIa family of Phosphatidylinositol-3-kinases, which create second messenger lipids that regulate a wide range of downstream signaling pathways involved in cell growth, survival and migration. Tiosano et al. (2019) identified the first monogenic disorder associated with biallelic PIK3C2A loss-of-function variants (oculoskeletodental syndrome). The novel syndrome was characterized by short stature, coarse facial features, ocular and skeletal abnormalities. This report describes two additional siblings affected by the PIK3C2A-related syndrome, confirms core clinical features, establishes intrafamilial variability and expands the phenotype to include proteinuria.