EIF2AK4 mutation as "second hit" in hereditary pulmonary arterial hypertension.
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.
['Eichstaedt|Christina A|CA|', 'Song|Jie|J|', 'Benjamin|Nicola|N|', 'Harutyunova|Satenik|S|', 'Fischer|Christine|C|', 'Grünig|Ekkehard|E|', 'Hinderhofer|Katrin|K|']
D000328:Adult D000369:Aged, 80 and over D062186:Arterial Pressure D052006:Bone Morphogenetic Protein Receptors, Type II D004252:DNA Mutational Analysis D005260:Female D056726:Genetic Association Studies D020022:Genetic Predisposition to Disease D040941:Heredity D006801:Humans D006976:Hypertension, Pulmonary D008297:Male D008875:Middle Aged D009154:Mutation D010375:Pedigree D019683:Penetrance D010641:Phenotype D017346:Protein Serine-Threonine Kinases D011651:Pulmonary Artery D055815:Young Adult
Hereditary pulmonary arterial hypertension Next generation sequencing Pulmonary veno-occlusive disease Two-gene model