PIK3R2 – Megalencephaly-Polymicrogyria-Polydactyly-Hydrocephalus Syndrome

PIK3R2 encodes the p85β regulatory subunit of class IA phosphoinositide 3-kinase. Pathogenic variants in PIK3R2 have been linked to megalencephaly-polymicrogyria-polydactyly-hydrocephalus (MPPH) syndrome, a rare neurodevelopmental disorder characterized by brain overgrowth, cortical malformations, postaxial polydactyly, and ventriculomegaly.

Inheritance of PIK3R2-related MPPH is autosomal dominant, typically arising from de novo missense variants. Affected individuals present with megalencephaly (HP:0001355), perisylvian polymicrogyria (HP:0012650), intellectual disability (HP:0001249), and focal impaired awareness seizures (HP:0002384).

Genetic evidence includes four unrelated probands with de novo PIK3R2 variants in the SH2 domain: three previously reported variants (c.1117G>A (p.Gly373Arg), c.1126A>G (p.Lys376Glu), c.1202T>C (p.Leu401Pro)) and one novel c.1669G>C (p.Asp557His) affecting the PI3K catalytic interface (PMID:26860062). All variants are absent from population controls and arose de novo.

Segregation data are limited to de novo occurrences without additional familial transmission. No reports of affected second-degree relatives with segregating PIK3R2 variants have been described.

Functional studies support a gain-of-function mechanism. A knock-in mouse model of the most frequent human variant p.Gly373Arg exhibits brain overgrowth, cortical lamination defects, and EEG abnormalities concordant with human MPPH (PMID:32856318). These mice display hyperactivation of the PI3K-AKT pathway, mirroring the proposed pathogenic mechanism.

Overall, the association between PIK3R2 and MPPH syndrome is classified as Strong based on multiple de novo probands and concordant in vivo functional data. Genetic testing for PIK3R2 variants is clinically useful for diagnosis, management, and genetic counseling in MPPH.

References

• European Journal of Human Genetics • 2016 • De novo PIK3R2 variant causes polymicrogyria, corpus callosum hyperplasia and focal cortical dysplasia PMID:26860062
• Annals of Neurology • 2020 • PIK3R2/Pik3r2 Activating Mutations Result in Brain Overgrowth and EEG Changes PMID:32856318

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