Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension

Media type: E-Article
Title: Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension
Contributor: Hadinnapola, Charaka; Bleda, Marta; Haimel, Matthias; Screaton, Nicholas; Swift, Andrew; Dorfmüller, Peter; Preston, Stephen D.; Southwood, Mark; Hernandez-Sanchez, Jules; Martin, Jennifer; Treacy, Carmen; Yates, Katherine; Bogaard, Harm; Church, Colin; Coghlan, Gerry; Condliffe, Robin; Corris, Paul A.; Gibbs, Simon; Girerd, Barbara; Holden, Simon; Humbert, Marc; Kiely, David G.; Lawrie, Allan; Machado, Rajiv; [...]
imprint: Ovid Technologies (Wolters Kluwer Health), 2017
Published in: Circulation
Language: English
DOI: 10.1161/circulationaha.117.028351
ISSN: 1524-4539; 0009-7322
Keywords: Physiology (medical) ; Cardiology and Cardiovascular Medicine
Origination:
Footnote:
Description: <jats:sec> <jats:title>Background:</jats:title> <jats:p> 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 ( <jats:italic>BMPR2</jats:italic> ) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene ( <jats:italic>EIF2AK4</jats:italic> ) 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. </jats:p> </jats:sec> <jats:sec> <jats:title>Methods:</jats:title> <jats:p> 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 <jats:italic>BMPR2</jats:italic> and biallelic <jats:italic>EIF2AK4</jats:italic> 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 <jats:italic>sorting intolerant from tolerant</jats:italic> predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. </jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p> Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in <jats:italic>BMPR2</jats:italic> were identified in 130 patients (14.8%). Biallelic mutations in <jats:italic>EIF2AK4</jats:italic> 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 <jats:italic>EIF2AK4</jats:italic> mutations. These patients had a reduced transfer coefficient for carbon monoxide (K <jats:sc>co</jats:sc> ; 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 <jats:italic>EIF2AK4</jats:italic> mutations. However, radiological assessment alone could not accurately identify biallelic <jats:italic>EIF2AK4</jats:italic> mutation carriers. Patients with PAH with biallelic <jats:italic>EIF2AK4</jats:italic> mutations had a shorter survival. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p> Biallelic <jats:italic>EIF2AK4</jats:italic> 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 K <jats:sc>co</jats:sc> 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. </jats:p> </jats:sec>
Access State: Open Access

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