Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension.
Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension.
复制标题
DOI：
10.1161/circulationaha.117.028351
复制
发表时间：
2017-11-21
期刊：
影响因子：
37.8
通讯作者：
Morrell NW
中科院分区：
文献类型：
--
作者：
Hadinnapola C;Bleda M;Haimel M;Screaton N;Swift A;Dorfmüller P;Preston SD;Southwood M;Hernandez-Sanchez J;Martin J;Treacy C;Yates K;Bogaard H;Church C;Coghlan G;Condliffe R;Corris PA;Gibbs S;Girerd B;Holden S;Humbert M;Kiely DG;Lawrie A;Machado R;MacKenzie Ross R;Moledina S;Montani D;Newnham M;Peacock A;Pepke-Zaba J;Rayner-Matthews P;Shamardina O;Soubrier F;Southgate L;Suntharalingam J;Toshner M;Trembath R;Vonk Noordegraaf A;Wilkins MR;Wort SJ;Wharton J;NIHR BioResource–Rare Diseases Consortium; UK National Cohort Study of Idiopathic and Heritable PAH;Gräf S;Morrell NW
肺动脉高压（PAH）是一种罕见的疾病，具有新的遗传基础。编码骨形态发生蛋白受体2（BMPR 2）的基因中的杂合突变是PAH最常见的遗传原因，而真核翻译起始因子2 α激酶4基因（EIF 2AK 4）中的双等位基因突变在肺静脉闭塞性疾病和肺毛细血管瘤病（PVOD/PCH）中有描述。在这里，我们确定了这些突变的频率，并在一个大型的临床诊断为PAH的患者队列中定义了基因型-表型特征。对来自特发性和遗传性PAH患者以及招募至NIHR BioResource -罕见疾病研究的PVOD/PCH的DNA进行全基因组测序。在对照数据集中具有< 1：10，000的次要等位基因频率并且被预测为有害的（通过CADD、PolyPhen-2和SIFT预测）BMPR 2和双等位基因EIF 2AK 4变体中的杂合变体被鉴定为潜在的因果关系。还采集了诊断时的表型数据。招募了864例特发性或遗传性PAH患者和16例PVOD/PCH患者。在130例患者（14.8%）中发现了BMPR 2突变。在5例临床诊断为PVOD/PCH的患者中鉴定了EIF 2AK 4的双等位基因突变。此外，9例临床诊断为PAH的患者携带双等位基因EIF 2AK 4突变。与无EIF 2AK 4突变的PAH患者相比，这些患者的一氧化碳转移系数降低（KCO：33 [IQR：30 - 35] %预测值），诊断时年龄较小（29 [23 - 38]岁），胸部计算机断层扫描显示小叶间隔增厚和纵隔淋巴结病更多。然而，单独的放射学评估不能准确地识别双等位基因EIF 2AK 4突变携带者。双等位基因EIF 2AK 4突变的PAH患者生存期较短。双等位基因EIF 2AK 4突变见于临床分类为特发性和遗传性PAH的患者。这些患者无法通过CT可靠地识别，但较低的KCO和年轻的诊断年龄表明了潜在的分子诊断。基因检测可以识别这些被错误分类的患者，允许适当的管理和肺移植的早期转诊。
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 and pulmonary capillary haemangiomatosis (PVOD/PCH). Here, we determined the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. Whole genome sequencing was performed on DNA from patients with idiopathic and heritable PAH, as well as PVOD/PCH recruited to the NIHR 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 CADD, PolyPhen-2 and SIFT predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. Eight hundred and sixty-four patients with idiopathic or heritable PAH and 16 with PVOD/PCH 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 PVOD/PCH. 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 [IQR: 30 - 35] % predicted) and younger age at diagnosis (29 [23 - 38] years) as well as more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest, compared to PAH patients without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. PAH patients with biallelic EIF2AK4 mutations had a shorter survival. Biallelic EIF2AK4 mutations are found in patients classified clinically as idiopathic and heritable PAH. These patients cannot be identified reliably by CT, but a low KCO and a young age of diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation.