The genetic blueprint behind PAH clinical features and prognosis

Introduction

Genetic predisposition plays a key role in the pathobiology of pulmonary arterial hypertension (PAH). With the expanding availability of next-generation sequencing (NGS), clinicians can now detect a broad spectrum of pathogenic and emerging variants across PAH-associated genes. However, the true clinical consequences of these findings – particularly their impact on phenotype and prognosis – remain undefined.

Aim

To characterize the genetic landscape of a contemporary PAH cohort and compare clinical features and outcomes between patients (pts) with and without identified genetic variants.

Methods

Retrospective, single-center study of pts with PAH who underwent genetic testing (GT) from 2012 to 2025. Testing consisted of BMPR2 sequencing or multigene NGS panels. Baseline patient characteristics were collected at diagnosis. Pts with a positive GT (GT+) were compared to those without identified variants (GT–). Group comparisons were performed with t-tests or Mann–Whitney tests, as appropriate. Time to all-cause death/hospitalization was assessed with Kaplan–Meier and log-rank analysis.

Results

Of 78 GT performed, 63 generated reportable results. A total of 24 variants were identified across multiple PAH-associated genes – BMPR2 (50%), ACVRL1 (13%), EIF2AK4 (13%), ABCC8 (4%), FOXF1 (4%), SMAD9 (4%), KDR (4%), ENG (4%), and GDF2 (4%). The overall diagnostic yield was 38%; pathogenic (P) / likely pathogenic (LP) variants were detected in 14 pts (22% yield).

Compared with GT– pts (n=36), GT+ pts (n=21) were younger at diagnosis (42 vs. 51 years, p=0.027). Baseline WHO functional class, NTproBNP and 6-minute walk distance were similar between groups. Echocardiographic parameters were comparable except for a significantly lower TAPSE/sPAP ratio in GT+ pts (0.24±0.14 vs. 0.40±0.15 mm/mmHg, p=0.018). Hemodynamically, GT+ pts had numerically higher pulmonary vascular resistance (14.1 vs. 10.6 WU, p=NS) and significantly lower cardiac index (1.86 vs. 2.56 L/min/m², p=0.004).

During a mean follow-up of 4.2 years, no differences were observed between GT+ and GT– pts in all-cause mortality (p=0.777) or in the composite outcome of death or hospitalization (p=0.654). Stratification by type of variant (P/LP vs. VUS/negative) likewise revealed no differences in event-free survival.

Conclusion

GT demonstrated a robust diagnostic yield and identified variants across a wide range of PAH-associated genes. GT+ pts were younger and exhibited a more adverse hemodynamic profile – particularly regarding right ventricular–pulmonary arterial coupling. Despite these differences, genetic status did not translate into measurable differences in long-term clinical outcomes. These findings underscore the complexity of genetic influences in PAH and emphasize the need for larger cohorts to clarify how specific variants interact with phenotype, treatment response and prognosis.For image description, please refer to the figure legend and surrounding text.