Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension
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jats:sec jats:titleBackground:</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:italicBMPR2</jats:italic> ) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene ( jats:italicEIF2AK4</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:titleMethods:</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:italicBMPR2</jats:italic> and biallelic jats:italicEIF2AK4</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:italicsorting 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:titleResults:</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:italicBMPR2</jats:italic> were identified in 130 patients (14.8%). Biallelic mutations in jats:italicEIF2AK4</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:italicEIF2AK4</jats:italic> mutations. These patients had a reduced transfer coefficient for carbon monoxide (K jats:scco</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:italicEIF2AK4</jats:italic> mutations. However, radiological assessment alone could not accurately identify biallelic jats:italicEIF2AK4</jats:italic> mutation carriers. Patients with PAH with biallelic jats:italicEIF2AK4</jats:italic> mutations had a shorter survival. </jats:p> </jats:sec> jats:sec jats:titleConclusions:</jats:title> jats:p Biallelic jats:italicEIF2AK4</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:scco</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>
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1524-4539
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British Heart Foundation (None)
British Heart Foundation (None)
Department of Health (NIHR SENIOR INVESTIGATOR AWARD)
Department of Health (via National Institute for Health Research (NIHR)) (NF-SI-0514-10086)
Cambridge University Hospitals NHS Foundation Trust (CUH) (146281)