Gene. 2026 Oct 25:150453. doi: 10.1016/j.gene.2026.150453. Online ahead of print.
ABSTRACT
Pulmonary arterial hypertension (PAH) exhibits greater genetic enrichment in children than in adults; however, genotype-phenotype correlations in Chinese paediatric PAH remain poorly defined. We performed targeted exome sequencing of 16 PAH-associated genes in 154 children with PAH at Beijing Anzhen Hospital (2010-2023) and interpreted variants under a calibrated, point-based ACMG/AMP framework. Pathogenic or likely pathogenic (P/LP) variants were identified in 38 patients (24.7 %): 23 BMPR2 (60.5 %), 7 TBX4 (18.4 %), 5 ACVRL1 (13.2 %), 2 SOX17 (5.3 %), and 1 GDF2 (2.6 %). Thirty variants were upgraded from the baseline automated InterVar classification, including five BMPR2 missense variants reclassified through the PP2 criterion. An additional 42 patients (27.3 %) harboured variants of uncertain significance (VUS) only. P/LP carriers presented with more severe baseline haemodynamics than benign or likely benign (B/LB) carriers, with higher pulmonary vascular resistance indices and lower cardiac indices. Among the 43 patients with available follow-up data, P/LP carriers exhibited significantly worse event-free survival than B/LB carriers and non-carriers (10-year estimate 47.7 % vs. 78.5 %; HR 3.70, 95 % CI 1.04-13.20; log-rank p = 0.0309), an effect largely attributable to BMPR2 variants (HR 4.83, 95 % CI 1.29-18.04). In contrast, VUS carriers resembled B/LB carriers and non-carriers (HR 0.84, p = 0.8436). Thus, the calibrated variant-classification framework substantially increased the diagnostic yield in Chinese paediatric PAH, uncovered an under-recognised contribution of BMPR2 missense variants, and enabled prognostic stratification across the three-tier pathogenicity spectrum.
PMID:42927780 | DOI:10.1016/j.gene.2026.150453