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

Charaka Hadinnapola, Marta Bleda, Matthias Haimel, Nicholas Screaton, Andrew Swift, Peter Dorfmüller, Stephen D. Preston, Mark Southwood, Jules Hernandez-Sanchez, Jennifer Martin, Carmen Treacy, Katherine Yates, Harm Bogaard, Colin Church, Gerry Coghlan, Robin Condliffe, Paul A. Corris, Simon Gibbs, Barbara Girerd, Simon HoldenMarc Humbert, David G. Kiely, Allan Lawrie, Rajiv Machado, Robert MacKenzie Ross, Shahin Moledina, David Montani, Michael Newnham, Andrew Peacock, Joanna Pepke-Zaba, Paula Rayner-Matthews, Olga Shamardina, Florent Soubrier, Laura Southgate, Jay Suntharalingam, Mark Toshner, Richard Trembath, Anton Vonk Noordegraaf, Martin R. Wilkins, Stephen J. Wort, John Wharton, Stefan Gräf, Nicholas W. Morrell, NIHR BioResource–Rare Diseases Consortium; UK National Cohort Study of Idiopathic and Heritable PAH

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)2022-2033
Number of pages12
JournalCirculation
Volume136
Issue number21
DOIs
Publication statusPublished - 21 Nov 2017

Cite this

Hadinnapola, C., Bleda, M., Haimel, M., Screaton, N., Swift, A., Dorfmüller, P., ... NIHR BioResource–Rare Diseases Consortium; UK National Cohort Study of Idiopathic and Heritable PAH (2017). Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension. Circulation, 136(21), 2022-2033. https://doi.org/10.1161/CIRCULATIONAHA.117.028351