Abstract Idiopathic pulmonary arterial hypertension (IPAH) is a rare and progressive disease characterized by elevated pulmonary vascular resistance and right ventricular failure. While mutations inBMPR2, ACVRL1, and SMAD9 explain many familial or idiopathic cases, a substantial proportion of patients lack these classical variants. To explore additional contributors, we examinedgenetic alterations reported in experimental pulmonary hypertension (PH) models as potential drivers of human IPAH. Between 2023 and 2024, six IPAH patients underwent extended next-generation sequencing (NGS). Variants were classified by ACMG criteria and correlated with clinical features. Two patients harbored BMPR2 or ENG mutations consistent with known PAHmechanisms, but the remaining carried non-canonical variants. Case 2 (TGFBR1) linked IPAH to immune-related comorbidities; Case 3 (FOXF1) suggested incomplete penetrance in pediatricIPAH; Case 4 (NOTCH3 and CELA2A) implicated smooth muscle proliferation and elastin remodeling; Case 5 (ENG) overlapped with hereditary hemorrhagic telangiectasia; and Case 6, withscleroderma-associated IPAH but no mutations, provided contrast to genetically driven phenotypes. These findings expand the genetic spectrum of IPAH beyond classical PAH-associatedgenes. Variants in TGFBR1, FOXF1, NOTCH3, CELA2A, and ENG—though not routinely screened—are functionally linked to endothelial dysfunction, abnormal vascular remodeling, immunedysregulation, and extracellular matrix degradation in preclinical studies. Of particular interest, NOTCH3 promotes pulmonary arterial smooth muscle proliferation and resistance toapoptosis, while CELA2A may mediate elastin degradation. Such mechanisms may accelerate disease even without primary BMPR2 mutations. This case series supports the concept thatIPAH is genetically and pathophysiologically heterogeneous. Non-canonical variants may underlie disease in patients with early onset, systemic comorbidities, or syndromic features.Expanded sequencing panels and functional validation are therefore warranted to uncover novel disease pathways and therapeutic targets. Recognition of these alternative mechanismscould enable individualized risk stratification and inform future precision therapies beyond the BMPR2 axis.Conclusively,IPAH may arise from a wider range of genetic disruptions thanpreviously recognized. Incorporating extended gene panels into clinical practice may reveal hidden contributors, while mechanistic studies of non-classical genes such as NOTCH3 andCELA2A could provide opportunities for innovative treatment strategies. This abstract is funded by: None
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