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

Hadinnapola, C; Bleda, M; Haimel, M; Screaton, N; Swift, A; Dorfmüller, P; Preston, SD; Southwood, M; Hernandez-Sanchez, J; Martin, J; et al. 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; Noordegraaf, AV; Wilkins, MR; Wort, SJ; Wharton, J; NIHR BioResource–Rare Diseases Consortium; UK National Cohort St, ; Gräf, S; Morrell, NW (2017) Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension. Circulation, 136 (21). pp. 2022-2033. ISSN 1524-4539 https://doi.org/10.1161/CIRCULATIONAHA.117.028351
SGUL Authors: Southgate, Laura

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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.

Item Type: Article
Additional Information: © 2017 The Authors. Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. 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.
Keywords: genetics, hypertension, pulmonary, mutation, prognosis, pulmonary veno-occlusive disease, EIF2AK4, genetics, human, prognosis, pulmonary hypertension, pulmonary veno-occlusive disease, Cardiovascular System & Hematology, 1103 Clinical Sciences, 1102 Cardiovascular Medicine And Haematology, 1117 Public Health And Health Services
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) > Cell Sciences (INCCCS)
Journal or Publication Title: Circulation
ISSN: 1524-4539
Language: eng
Dates:
DateEvent
21 November 2017Published
28 September 2017Published Online
25 August 2017Accepted
Publisher License: Creative Commons: Attribution 3.0
Projects:
Project IDFunderFunder ID
UNSPECIFIEDNational Institute of Health ResearchUNSPECIFIED
UNSPECIFIEDBritish Heart Foundationhttp://dx.doi.org/10.13039/501100000274
UNSPECIFIEDMedical Research Councilhttp://dx.doi.org/10.13039/501100000265
PubMed ID: 28972005
Go to PubMed abstract
URI: http://openaccess.sgul.ac.uk/id/eprint/109218
Publisher's version: https://doi.org/10.1161/CIRCULATIONAHA.117.028351

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