The prevalence and significance of the EIF2AK4 variants in the patients with pulmonary arterial hypertension

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Abstract Background Eukaryotic translation initiation factor 2 alpha kinase 4 (EIF2AK4) has been reported to be the causative gene of pulmonary veno-occlusive disease (PVOD).[1] Although some patients with pulmonary arterial hypertension (PAH) also carry the EIF2AK4 variants, its importance remains unclear. Purpose The purpose of this study was to evaluate the prevalence and significance of EIF2AK4 variants in patients with PAH. Methods The whole exome sequencing were performed in total 162 patients with idiopathic or heritable PAH. The clinical data including the high-resolution CT scanning, pulmonary function test, laboratory data at diagnosis, and therapeutic response to pulmonary vasodilator were evaluated. Results We identified the heterozygous variants of EIF2AK4 in 6 (3.7%) patients. Among them, 2 patients also had bone morphogenetic protein receptor type 2 (BMPR2) variants which were defined as pathogenic by American College of Medical Genetics and Genomics classification. The other 4 patients did not have known PAH associated gene variants. Although the typical findings of PVOD such as interlobular septal thickening and enlarged mediastinal lymph nodes, were not identified by the CT scanning, the median percent diffusing capacity for carbon monoxide of patients with EIF2AK4 heterozygous variants was reduced to 45.6%. In addition, 4 of 6 patients received prostacyclin injection therapy because oral combination therapy was ineffective, and 2 patients died. Moreover, none of the 6 patients reached mean pulmonary arterial pressure≤30 mmHg despite the combination therapy. We also identified homozygous EIF2AK4 variants in 2 patients with PAH. They did not have the known causative variants of PAH. CT scanning at diagnosis did not detect any characteristic of PVOD in either of the two patients. Although the pulmonary vasodilator was initiated without induction of pulmonary edema, one patient was refractory to the therapy. Conclusions The genetic analysis is crucial for accurate diagnosis even in patients diagnosed with PAH because heterozygous or homozygous variants in EIF2AK4 could be involved in the disease pathology.

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