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PIK3CA encodes the p110α catalytic subunit of class IA phosphoinositide 3-kinase which regulates cell growth, survival, and angiogenesis. Somatic activating variants in PIK3CA have been consistently identified in vascular malformations, defining a mosaic overgrowth phenotype and guiding targeted therapy.
A comprehensive cohort of 319 vascular malformations revealed pathogenic mosaic PIK3CA mutations in 80 cases (25%) across diverse lesion types (PMID:30677207). In a separate multi-center series of 115 patients, 21 (18%) harbored activating PIK3CA variants (PMID:33105631). A Chinese pediatric cohort detected somatic PIK3CA variants in 29 of 67 patients (43%), including hotspots in both helical and kinase domains (PMID:37658401).
The variant spectrum is dominated by recurrent hotspot substitutions in the helical (c.1624G>A (p.Glu542Lys), c.1633G>A (p.Glu545Lys)) and kinase (c.3140A>T (p.His1047Leu)) domains. These gain-of-function changes occur at low variant allele fractions (<10%) in lesional tissue, underscoring the need for sensitive molecular assays such as deep targeted NGS and cfDNA liquid biopsy (PMID:35807022).
Inheritance is non-Mendelian, arising from post-zygotic somatic mosaicism without familial segregation (affected relatives 0). No germline inheritance has been documented in isolated vascular malformations.
Functional studies demonstrate that hotspot PIK3CA variants increase lipid kinase activity, AKT phosphorylation, and downstream mTOR signaling in cell models (PMID:15930273; PMID:19805105). Patient-derived lesions shrink upon treatment with the p110α-specific inhibitor alpelisib, correlating molecular inhibition with clinical improvement (PMID:38265477).
No conflicting evidence disputes the PIK3CA–vascular malformation association. Collectively, genetic mosaic data, mechanistic assays, and successful targeted therapy establish a robust gene–disease link. Key take-home: Screening for PIK3CA mosaic variants is critical for accurate diagnosis and enables effective use of PI3K inhibitors in vascular malformation management.
Gene–Disease AssociationStrongSomatic mosaic PIK3CA variants in ≥80 probands across independent cohorts with concordant functional and therapeutic response data Genetic EvidenceStrongSomatic mosaic PIK3CA gain-of-function mutations in 80/319 patients (PMID:30677207) and 21/115 patients (PMID:33105631), with recurrent hotspots Functional EvidenceModerateIn vitro and clinical studies demonstrate gain-of-function PI3K activation by hotspot variants and lesion regression with PI3K inhibitor alpelisib (PMID:38265477; PMID:15930273) |