Phenotypes Associated With EIF2AK4 Mutations in PAH

An illustration of a DNA strand
An illustration of a DNA strand
The frequency of eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) mutations in patients with pulmonary arterial hypertension was investigated.

Genetic testing to identify mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) in patients with pulmonary arterial hypertension (PAH) may help facilitate appropriate management of high-risk individuals, according to the results of a recent study published in Circulation.

Typically, heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) are the most common cause of PAH, whereas EIF2AK4 mutations are usually detected in individuals with pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis (PVOD/PCH).

The investigators sought to determine the frequency of EIF2AK4 mutations and to characterize the genotypic-phenotypic features in a large cohort of 880 patients with a clinical diagnosis of idiopathic or heritable PAH (n=864) or PVOD/PCH (n=16). Whole genome sequencing was performed on DNA from all patients, who were recruited to the National Institute of Health Research BioResource — Rare Disease (BRIDGE) study.

Mutations in BMPR2 were detected in 130 patients (14.8%). Biallelic EIF2AK4 mutations were identified in 5 patients with PVOD/PCH. Additionally, 9 patients with PAH exhibited biallelic EIF2AK4 mutations. These individuals were a younger age at diagnosis compared with those without the variants.

Moreover, study participants with PAH and EIF2AK4 mutations exhibited a significantly reduced transfer coefficient for carbon monoxide (KCO: 33% predicted [30%-35% predicted]) compared with BMPR2 mutation carriers (81% predicted [73%-92% predicted]; P <.001) and those with PAH and no identified mutation (KCO: 71% predicted [51%-85% predicted]; P =.001).

Radiologic assessment alone could not accurately recognize biallelic EIF2AK4 mutation carriers. Survival among patients with PAH and EIF2AK4 mutations was shorter than survival among those without the genetic mutation.

Related Articles

The investigators concluded that EIF2AK4 mutations are present in patients with idiopathic or heritable PAH, but current computed tomography scans are unable to reliably identify these individuals. A low KCO and a young age at diagnosis are both suggestive of an underlying molecular diagnosis. Genetic testing should help identify potentially misclassified patients, permitting application of appropriate management strategies.


Hadinnapola C, Bleda M, Haimel M, et al; NIHR BioResource – Rare Diseases Consortium & UK National Cohort Study of Idiopathic and Heritable PAH. Phenotypic characterisation of EIF2AK4 mutation carriers in a large cohort of patients diagnosed clinically with pulmonary arterial hypertension [published online September 28, 2017]. Circulation. doi: 10.1161/CIRCULATIONAHA.117.028351.