Differentiating pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH) from idiopathic or heritable pulmonary arterial hypertension (IPAH and HPAH) is important clinically. Mutations in eukaryotic translation initiation factor 2 alpha kinase 4 (EIF2AK4) cause heritable PVOD and PCH whereas mutations in other genes cause HPAH. The aim of this study is to describe the frequency of pathogenic EIF2AK4 mutations in patients diagnosed clinically with IPAH or HPAH.
We performed Sanger sequencing and deletion/duplication analysis to detect mutations in the BMPR2 gene on 81 patients diagnosed at 30 North American medical centers with IPAH (n=72) or HPAH (n=9). BMPR2 mutation negative patients (n=67) were sequenced for mutations in four other genes (ACVRL1, ENG, CAV1, KCNK3) known to cause HPAH. Patients negative for mutations in all known PAH genes (n=66) were then sequenced for mutations in EIF2AK4. We assessed the pathogenicity of EIF2AK4 mutations and reviewed clinical characteristics of patients with pathogenic EIF2AK4 mutations.
Pathogenic BMPR2 mutations were identified in 8 of 72 (11.1%) IPAH patients and 6 of 9 (66.7%) HPAH patients. We identified a novel homozygous EIF2AK4 mutation (c.257+4A>C) in 1 of 9 (11.1%) patients diagnosed with HPAH. The novel EIF2AK4 mutation (c.257+4A>C) was homozygous in two sisters with severe pulmonary hypertension. None of the 72 IPAH patients had bi-allelic EIF2AK4 mutations.
Pathogenic bi-allelic EIF2AK4 mutations are identified rarely in patients diagnosed with HPAH. Identification of pathogenic bi-allelic EIF2AK4 mutations can aid clinicians in differentiating HPAH from heritable PVOD or PCH.