Testing for EIF2AK4 Mutations May Help Distinguish Between PAH and Other Severe PH Diseases, Study Says

Patients with mutations in the EIF2AK4 gene have worse outcomes than others with pulmonary arterial hypertension (PAH), researchers report, suggesting that genetic tests be given these people — often diagnosed with PAH — to determine if they actually have pulmonary vena-occlusive disease (PVOD) or pulmonary capillary hemangiomatosis (PCH) and can be treated accordingly.

Their study “Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension” was published in the journal Circulation.  

PAH is a rare disorder often associated with underlying conditions such as connective tissue disease or congenital disease. Related, but distinct, forms of pulmonary hypertension include PVOD and PCH. But standard clinical and radiological tests are often unable to distinguish between PAH and PVOD or PCH. But PVOD and PCH patients require more intensive treatment since the prognosis of these diseases is more severe, meaning an early and accurate diagnosis is important.

Previous studies have identified mutations in the gene coding for the bone morphogenetic protein type 2 receptor (BMPR2) as the most common genetic cause of PAH. These mutations are found in approximately 17% of individuals with idiopathic PAH, and 82% of those with a family history of the disease.

However, mutations in BMPR2 gene have also been reported in people with PVOD — a rare form of pulmonary hypertension caused by progressive blockage of small veins in the lungs — making this mutation unreliable distinguishing between the two disease types.

Researchers recently found that mutations in the gene coding the eukaryotic translation initiation factor 2 alpha kinase 4 (EIF2AK4) occur in both familial (100%) and sporadic (20% to 25%) cases of PVOD and PCH, a disease marked by extensive proliferation of pulmonary capillaries.  EIF2AK4 functions in response to cellular stress to increase the activity of specific genes.

In this study, mutations in BMPR2 and EIF2AK4 were examined using whole-genome sequencing. The research team then correlated them with disease subtype in a large group of patients  — 880 in total — of whom 864 were diagnosed with idiopathic or heritable PAH and 16 with PVOD or PCH. These patients were part of the National Institute for Health Research’s BRIDGE study in the U.K.

Mutations in BMPR2 were found in 130 patients (14.8%), while EIF2AK4 mutations, especially biallelic mutations (those occurring in both alleles, paternal and maternal, of a gene) were found in nine PAH-diagnosed patients and five others with a clinical diagnosis of PVOD or PCH.

The nine PAH patients also had characteristics consistent with PVOD and PCH, the researchers reported, such as a reduced transfer coefficient for carbon monoxide (KCO, a measure of how well the lungs ventilate) and a younger age at diagnosis (23–38 years) compared to PAH patients without EIF2AK4 mutations. These nine also showed changes in the lungs, interlobular septal thickening and mediastinal lymphadenopathy seen on computed chest tomography, consistent with more severe disease.

These findings suggest that EIF2AK4 mutations are specific to PVOD and PCH. Identifying these mutations in patients diagnosed with PAH could help in detecting the other diseases.

“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,” the study concludes.

Because PVOD and PCH are severe and require quick intervention, genetic testing could help patients get appropriate treatment, guiding disease management and offering earlier referrals for lung transplant.