A new mutation in the EIF2AK4 gene in familial pulmonary veno-occlusive disease

Pulmonary veno-occlusive disease (PVOD) is a rare type of pulmonary arterial hypertension (PAH) characterized by remodeling of septal veins and preseptal venules.¹ In comparison with PAH, it is more severe, has a worse prognosis, and requires a different therapeutic approach. Detection of familial or sporadic mutations in the EIF2AK4 gene can aid in establishing a correct diagnosis.^2-4

A 29-year-old, previously healthy woman was admitted to our center with progressive exertional dyspnea (World Health Organization functional class III) and cyanosis. Echocardiography showed signs of severe right ventricular overload (Figure 1A). Ventilation / perfusion lung scintigraphy excluded thromboembolic etiology of pulmonary hypertension. Results of the pulmonary function tests were normal, and the lung diffusion capacity for carbon monoxide was severely reduced. Right heart catheterization confirmed the diagnosis of nonreactive precapillary pulmonary hypertension with a mean pulmonary artery pressure of 42 mm Hg, pulmonary vascular resistance of 14 WU, and a decreased cardiac index of 1.6 l/min/m². High-resolution computed tomography of the chest showed diffuse, multifocal ground-glass opacities and interlobular septal thickening (Figure 1B). Despite the possibility of PVOD, we initiated treatment with low doses of subcutaneous treprostinil, intravenous loop diuretics, and passive oxygen therapy due to the severe pressure overload of the right heart, and we referred the patient to the lung transplant center. After 2 months of initial improvement she was readmitted with clinical deterioration including resting dyspnea, ascites, and low systemic blood pressure. Despite intensive treatment including extracorporeal membrane oxygenation, the patient died in the intensive care unit.

Using the genetic material of the patient and her first-degree family, the EIF2AK4 gene analysis was performed. Since the patient’s father had died prematurely of an unknown cause, a sample of his genetic material could not be obtained. Next-generation sequencing was used to assess the mutation occurrence and the results were then confirmed with Sanger sequencing. MEDLINE, ClinVar, ExAC, 1000 Genomes Project, and dbSNP databases were searched to identify the discovered mutations.

The analysis showed a biallelic frameshift mutation in the exon 35 of the EIF2AK4 gene with a deletion of the TTTG fragment that had not been described before. Among the family members of the patient, 3 brothers and the mother were heterozygous for this mutation and did not develop the disease (Figure 1C). Details of the frameshift variant are shown in Figure 1D. An analysis of previously reported whole-exome sequencing data from a French referral center⁵ also detected biallelic mutations in EIF2AK4 in all familial PVOD cases; the mutations were present in a heterozygous state in unaffected parents. Most of them were stop codons, frameshift mutations, or splicing variants in various regions of the EIF2AK4 gene that—either in a homozygous or compound-heterozygous state—disrupted the function of the gene and were associated with a clinical presentation of PVOD.

The identification of a previously unknown mutation in the EIF2AK4 gene in the patient’s family members suggests a hereditary origin of the disease. Early detection of the mutation in apparently sporadic cases may facilitate further treatment decisions, including urgent referral for lung transplantation, and allow for adequate genetic counseling of other family members.¹