Genotype-phenotype correlation in vascular malformations and implications for targeted therapy

Molecular studies have clarified the causes of vascular malformations and enabled targeted treatment. The broad phenotypic variation associated with variants in the same gene, however, complicates translation of molecular findings into clinical decisions. This narrative review examines genotype–phenotype relationships and their implications for diagnosis, treatment, and outcome assessment. PI3K–AKT–mTOR alterations are common in venous, lymphatic, and overgrowth disorders, while RAS–MAPK alterations are frequent in arteriovenous malformations. Gαq/11 signaling is implicated in capillary and neurocutaneous malformations, while distinct mechanisms underlie hereditary hemorrhagic telangiectasia and cerebral cavernous malformations. Within these groups, variant function and the distribution of variant-bearing cells may contribute to phenotypic variation. Clinical phenotype and suspected variant distribution guide initial specimen selection. Molecular findings then inform family testing and surveillance. Treatment decisions begin with disease extent, symptoms, organ risk, and patient goals; genotype then helps inform systemic-agent selection. Clinical evidence is most extensive for sirolimus in complicated slow-flow anomalies and alpelisib in severe PIK3CA -related overgrowth, although study designs and response definitions differ. Benefit is assessed through imaging, symptoms, function, organ-specific measures, patient-reported outcomes, and adverse effects. Integrating molecular findings with tissue involvement and clinical burden can refine diagnosis, surveillance, and treatment decisions. Improving prediction for individual patients requires prospective studies with consistent molecular characterization, clinically meaningful outcomes, and long-term safety follow-up.