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Background  Mutations in the  eukaryotic translation initiation factor 2α kinase 4  ( EIF2AK4 ) gene have recently been identified in recessively inherited veno-occlusive disease. In this study we assessed if  EIF2AK4  mutations occur also in a family with autosomal dominantly inherited pulmonary arterial hypertension (HPAH) and incomplete penetrance of  bone morphogenic protein receptor 2  ( BMPR2 ) mutations.    Methods  Clinical examinations in a family with 10 members included physical examination, electrocardiogram, (stress)-echocardiography and lung function. Manifest PAH was confirmed by right heart catheterisation in three affected subjects. Genetic analysis was performed using a new PAH-specific gene panel analysis with next generation sequencing of all known PAH and further candidate genes. Identified variants were confirmed by Sanger sequencing.    Results  All living family members with manifest HPAH carried two pathogenic heterozygous mutations: a frame shift mutation in the  BMPR2  gene and a novel splice site mutation in the  EIF2AK4  gene. Two family members who carried the  BMPR2  mutation only did not develop manifest HPAH.    Conclusions  This is the first study suggesting that  EIF2AK4  can also contribute to autosomal dominantly inherited HPAH. Up to now it has only been identified in a recessive form of HPAH. Only those family members with a co-occurrence of two mutations developed manifest HPAH. Thus, the  EIF2AK4  and  BMRPR2  mutations support the “second hit” hypothesis explaining the variable penetrance of HPAH in this family. Hence, the assessment of all known PAH genes in families with a known mutation might assist in predictions about the clinical manifestation in so far non-affected mutation carriers.

EIF2AK4 mutation as “second hit” in hereditary pulmonary arterial hypertension