Whole exome sequencing unravels genetic architecture and its clinical implications in pediatric pulmonary arterial hypertension

Abstract

Background: Pulmonary arterial hypertension (PAH) is a severe disease with significant genetic predisposition. While genetic architecture and clinical implications in pediatric PAH remain unclear.

Methods: We retrospectively analyzed clinical and genetic data from 218 pediatric PAH patients including 115 idiopathic/heritable PAH (IPAH/HPAH) and 103 PAH associated with congenital heart disease (PAH-CHD) admitted to our center between 2011 and 2023.

Results: 50.0 % of the cohort carried genetic variations, with BMPR2 being the most prevalent (16.5 % in whole and 27.8 % in IPAH/HPAH). Compared to IPAH/HPAH, PAH-CHD showed a distinct mutation profile. Five hotspot mutation sites in 4 PAH-causing genes (BMPR2, ACVRL1, SOX17, KCNK3) were identified, resulting in altered charged amino acid residues or protein truncations. Patients with pathogenic or likely pathogenic (P/LP) mutations in definitive PAH-causing genes (affected mutation carriers) had a higher proportion of high-risk profile, more severe right ventricular enlargement and lower TAPSE, while patients with P/LP mutations in PAH-associated genes showed similar clinical features. Affected mutation carriers also had a poorer prognosis compared to non-carriers and received more aggressive therapeutic interventions. BMPR2 mutation carriers were older at diagnosis and had lower cardiac index compared to other mutation carriers.

Conclusion: This study unveiled a different genetic landscape of pediatric PAH in China, and underscored the importance of genetic screening for early risk stratification. A distinct mutation profile in PAH-CHD from IPAH/HPAH patients was found, which warrants further investigation on the identification of predisposing genes for each subpopulation, thus providing new insights into pathogenesis and therapeutic approaches of PAH.

Keywords: Genetics; Pediatrics; Pulmonary arterial hypertension; Pulmonary arterial hypertension associated with congenital heart disease; Whole-exome sequencing.