PIK3C2A – Oculocerebrodental Syndrome

PIK3C2A encodes a class II phosphatidylinositol-3-kinase involved in the generation of PI(3)P and PI(3,4)P₂ second messengers that regulate cell growth, survival, migration, and ciliogenesis. Biallelic loss-of-function variants in PIK3C2A were first linked to an autosomal recessive oculocerebrodental syndrome characterized by short stature, coarse facial features, ocular and skeletal anomalies. Subsequent reports have confirmed and expanded the phenotype, establishing a consistent clinical spectrum amenable to genetic testing for diagnostic decision-making.

In 2022, two siblings presented with short stature, coarse facies, ocular anomalies, skeletal dysplasia and proteinuria. Exome sequencing identified compound heterozygous PIK3C2A variants c.4381delC (p.Arg1461GlufsTer31) and c.1555C>T (p.Arg519Ter), each predicted to abolish kinase function ([PMID:35770347]). Both variants segregated with disease in the family, supporting recessive inheritance and confirming genotype–phenotype correlation.

In 2025, a fifth family was described in which affected individuals exhibited pulverulent cataracts and sensorineural hearing loss in addition to hallmark skeletal and facial dysmorphisms. Trio exome sequencing again revealed compound heterozygous LoF alleles in PIK3C2A, reinforcing the allelic series and expanding the clinical spectrum to include deafness ([PMID:40542664]).

Across these two unrelated families, three probands have been reported with biallelic PIK3C2A loss-of-function variants, demonstrating autosomal recessive inheritance and recurrence in sibships. The variant spectrum consists predominantly of frameshift and nonsense alleles leading to premature truncation and loss of kinase activity.

Functional characterization in patient-derived fibroblasts revealed normal PIK3C2A protein levels but markedly reduced enzymatic activity, defective primary cilia formation and maintenance, and decreased cellular proliferation—mechanistic evidence concordant with the human phenotype ([PMID:40542664]). These studies support haploinsufficiency of PIK3C2A as the pathogenic mechanism underlying oculocerebrodental syndrome.

No conflicting evidence has been reported. Together, genetic segregation and concordant functional assays provide moderate evidence for a causative role of PIK3C2A in autosomal recessive oculocerebrodental syndrome. Key Take-home: PIK3C2A sequencing should be pursued in patients with short stature, coarse facies, ocular and skeletal anomalies, and may guide early detection of associated hearing impairment and renal involvement.

References

• American journal of medical genetics. Part A • 2022 • Expanding the phenotype of PIK3C2A related syndrome: Report of two siblings with novel features and genotype. PMID:35770347
• Clinical genetics • 2025 • PIK3C2A-Related Clinical Phenotype and Cellular Charaterization Linked to Functional SHH Primary Cilia Defect. PMID:40542664

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