Phenotypic Characterisation of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically with Pulmonary Arterial Hypertension.

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Title: Phenotypic Characterisation of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically with Pulmonary Arterial Hypertension.
Authors: Hadinnapola, C
Bleda, M
Haimel, M
Screaton, N
Swift, AJ
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, SR
Girerd, B
Holden, S
Humbert, M
Kiely, DG
Lawrie, A
Machado, RD
MacKenzie Ross, R
Moledina, S
Montani, D
Newnham, M
Peacock, AJ
Pepke-Zaba, J
Rayner-Matthews, PJ
Shamardina, O
Soubrier, F
Southgate, L
Suntharalingam, J
Toshner, MR
Trembath, RC
Vonk Noordegraaf, A
Wilkins, MR
Wort, SJ
Wharton, J
Gräf, S
Morrell, NW
NIHR BioResource - Rare Diseases Consortium & UK National Cohort Study of Idiopathic and Heritable PAH
Item Type: Journal Article
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 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. Methods -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. Results -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. Conclusions -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.
Issue Date: 28-Sep-2017
Date of Acceptance: 25-Aug-2017
ISSN: 0009-7322
Publisher: American Heart Association
Start Page: 2022
End Page: 2033
Journal / Book Title: Circulation
Volume: 136
Issue: 21
Copyright Statement: © 2017 Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer. This is an open access article under the terms of the Creative Commons Attribution License (, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.
Sponsor/Funder: British Heart Foundation
Funder's Grant Number: RG68204 13/EE/0203 A092860
Keywords: EIF2AK4
genetics, human
pulmonary hypertension
pulmonary veno-occlusive disease
NIHR BioResource–Rare Diseases Consortium; UK National Cohort Study of Idiopathic and Heritable PAH
1103 Clinical Sciences
1102 Cardiovascular Medicine And Haematology
1117 Public Health And Health Services
Cardiovascular System & Hematology
Publication Status: Published
Open Access location:
Appears in Collections:National Heart and Lung Institute
Department of Medicine
Faculty of Medicine

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