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

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 RESEARCH ARTICLE P ulmonary arterial hypertension (PAH) is a heterogeneous and rare disorder that can be classified into idiopathic and heritable forms, associated with an underlying condition such as connective tissue disease or congenital heart disease or related to specific drugs and toxins. Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large1,2 In addition, p...

Time-resolved analysis of amino acid stress identifies eIF2 phosphorylation as necessary to inhibit mTORC1 activity in liver

“…Our study found that GCN2 governs important nutritional responses and, if dysfunctional, leads to altered whole body metabolism. It is tempting to speculate that as a result of this altered metabolism subjects bearing deleterious mutations in Gcn2 (EIF2AK4) gene have higher chances of developing metabolic conditions later in life such as pulmonary arterial hypertension (46). This work provides a foundation for personalized approaches in usage of other GCN2-activating drugs as well as dietary approaches.…”

Factors Associated with Heritable Pulmonary Arterial Hypertension Exert Convergent Actions on the miR-130/301-Vascular Matrix Feedback Loop

“…More recently, PAH patients have been reported to carry multiple gene mutations in at least two distinct pathogenic loci [36,37], furthering the hypothesis that these multiple hits may originate from the complex genetic inheritance of several mutations. Our findings of convergent, miR-130/301-specific actions of seemingly disparate factors relevant to hereditary PAH now offer new insights into this multiple-hit hypothesis.…”

Pulmonary Veno-Occlusive Disease: Pathogenesis, Risk Factors, Clinical Features and Diagnostic Algorithm—State of the Art

“…Recently, Hadinnapola et al [16] performed whole genome sequencing in 808 patients with IPAH, 56 with hPAH and 16 patients with PVOD/PCH. Bi-allelic mutations of EIF2AK4 were identified in 5 PVOD/PCH patients and in 9 IPAH patients (1%).…”

“…Bi-allelic mutations of EIF2AK4 were identified in 5 PVOD/PCH patients and in 9 IPAH patients (1%). Interestingly, EIF2AK4 positive IPAH patients, investigated both by Best et al [15] and by Hadinnapola et al [16], exhibited clinical symptoms that might be indicative of PVOD/PCH.…”