Background: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH.

Methods: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource–Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of <1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured.

Results: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (Kco; 33% [interquartile range, 30%–35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23–38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival.

Conclusions: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low Kco and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation.

背景：肺动脉高压（PAH）是一种罕见的疾病，具有新兴的遗传基础。编码骨形态发生蛋白受体2型（BMPR2）的基因中的杂合突变是PAH的最常见遗传原因，而真核翻译起始因子2α激酶4基因（EIF2AK4）中的双等位基因突变在肺静脉闭塞性疾病/肺毛细血管血管瘤病。在这里，我们确定了这些突变的频率，并定义了临床诊断为PAH的一大批患者的基因型-表型特征。

方法：对来自特发性和遗传性PAH和肺静脉闭塞性疾病/肺毛细血管性血管瘤病患者的DNA进行全基因组测序，该研究被纳入美国国立卫生研究院生物资源与稀有疾病研究机构。在对照数据集中，BMPR2和双等位基因EIF2AK4变体中等位基因频率＜1：10000的杂合子变体被预测为有害的（通过组合依赖注释的耗竭，PolyPhen-2和来自耐受性预测的不耐受分类）被确定为潜在的因果关系。诊断时的表型数据也被捕获。

结果：招募了644例特发性或遗传性PAH患者和16例肺静脉闭塞性疾病/肺毛细血管性血管病。130例患者中发现了BMPR2突变（14.8％）。在5例临床诊断为肺静脉闭塞性疾病/肺毛细血管血管瘤的患者中鉴定出EIF2AK4中的双等位基因突变。此外，有9位临床诊断为PAH的患者携带双等位基因EIF2AK4突变。这些患者的一氧化碳转移系数降低（K co; 与PAH患者相比，胸部X线计算机断层扫描显示，诊断时年龄预计为33％[四分位间距，30％–35％]，且较年轻（29岁；四分位间距，23-38岁），小叶间隔增厚和纵隔淋巴结肿大没有EIF2AK4突变。但是，仅靠放射学评估不能准确识别双等位基因EIF2AK4突变携带者。具有双等位基因EIF2AK4突变的PAH患者生存期较短。

结论：在临床上被分类为具有特发性和遗传性PAH的患者中发现了双等位基因EIF2AK4突变。这些患者不能通过计算机断层摄影术可靠地识别，但是低K co和诊断时年龄较小表明潜在的分子诊断。基因检测可以识别出这些错误分类的患者，从而可以进行适当的处​​理并尽早进行肺移植。