Clinical Interpretation of Genetic Testing in Pediatric Pulmonary Arterial Hypertension: From Molecular Findings to Action

ABSTRACT

Genetic testing has established diagnostic and family‐management roles in pediatric pulmonary arterial hypertension (PAH), with additional gene‐specific prognostic implications. This narrative review integrates contemporary pediatric cohorts, earlier childhood studies, adult evidence, and international recommendations to examine how molecular findings inform clinical care. Interpretation requires assessment of gene‐disease validity, variant classification, inheritance, and phenotypic concordance. Well‐supported results may refine disease classification, direct phenotypic evaluation, and enable cascade testing and surveillance. Pathogenic BMPR2 variants are associated with more severe hemodynamic disease and adverse outcomes across cohorts; this information complements longitudinal clinical risk assessment but does not precisely determine an individual child's course. TBX4 ‐related disease spans PAH, neonatal respiratory failure, and developmental lung disorders, sometimes with subtle skeletal findings. Biallelic EIF2AK4 variants can establish heritable pulmonary veno‐occlusive disease/pulmonary capillary hemangiomatosis and alter management. A variant of uncertain significance remains nondiagnostic, whereas a negative result must be interpreted within assay limitations. No germline variant has yet been validated to select a specific routine pediatric PAH drug. Genetic testing should therefore be linked to an explicit plan for diagnosis, gene‐informed risk assessment, phenotype‐directed care, and family follow‐up.