Jiang Dai-Ji, Yang Yi-Jia, Wang Yu-Zhen, Zhang Xu, Chan Wen-Xiu, Yu Ting-Ting, Chen Hao, Zhang Hao, Yan Yi, Fu Li-Jun
Heart Center and Shanghai Institute of Pediatric Congenital Heart Disease, Shanghai Children's Medical Center, National Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
Department of Cardiology, Shanghai Children's Medical Center, National Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China.
Int J Cardiol. 2025 Oct 15;437:133515. doi: 10.1016/j.ijcard.2025.133515. Epub 2025 Jun 12.
Pulmonary arterial hypertension (PAH) is a severe disease with significant genetic predisposition. While genetic architecture and clinical implications in pediatric PAH remain unclear.
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.
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.
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.
肺动脉高压（PAH）是一种具有显著遗传易感性的严重疾病。然而，儿科PAH的遗传结构和临床意义仍不清楚。
我们回顾性分析了2011年至2023年间入住我们中心的218例儿科PAH患者的临床和遗传数据，其中包括115例特发性/遗传性PAH（IPAH/HPAH）和103例与先天性心脏病相关的PAH（PAH-CHD）。
该队列中有50.0%的患者携带基因变异，其中BMPR2最为常见（在总体中占16.5%，在IPAH/HPAH中占27.8%）。与IPAH/HPAH相比，PAH-CHD表现出不同的突变谱。在4个PAH致病基因（BMPR2、ACVRL1、SOX17、KCNK3）中鉴定出5个热点突变位点，导致带电氨基酸残基改变或蛋白质截短。在明确的PAH致病基因中携带致病或可能致病（P/LP）突变的患者（受影响的突变携带者）具有较高比例的高危特征、更严重的右心室扩大和更低的三尖瓣环平面收缩期位移（TAPSE），而在PAH相关基因中携带P/LP突变的患者表现出相似的临床特征。与非携带者相比，受影响的突变携带者预后也较差，并且接受了更积极的治疗干预。与其他突变携带者相比，BMPR2突变携带者诊断时年龄更大，心脏指数更低。
本研究揭示了中国儿科PAH不同的遗传格局，并强调了基因筛查对早期风险分层的重要性。发现PAH-CHD患者与IPAH/HPAH患者的突变谱不同，这值得进一步研究每个亚群的易感基因，从而为PAH的发病机制和治疗方法提供新的见解。
