EIF2AK4 mutation as "second hit" in hereditary pulmonary arterial hypertension.
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.



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.



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.



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.
Center for Pulmonary Hypertension at the Thoraxclinic, University Hospital Heidelberg, Heidelberg, 69126, Germany.|Institute of Human Genetics, Heidelberg University, Im Neuenheimer Feld 366, 69120, Heidelberg, Germany.|Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany.
Christina A
CA
Eichstaedt
Center for Pulmonary Hypertension at the Thoraxclinic, University Hospital Heidelberg, Heidelberg, 69126, Germany.|Institute of Human Genetics, Heidelberg University, Im Neuenheimer Feld 366, 69120, Heidelberg, Germany.|Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany.
Jie
J
Song
Center for Pulmonary Hypertension at the Thoraxclinic, University Hospital Heidelberg, Heidelberg, 69126, Germany.|Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany.
Nicola
N
Benjamin
Center for Pulmonary Hypertension at the Thoraxclinic, University Hospital Heidelberg, Heidelberg, 69126, Germany.|Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany.
Satenik
S
Harutyunova
Institute of Human Genetics, Heidelberg University, Im Neuenheimer Feld 366, 69120, Heidelberg, Germany.
Christine
C
Fischer
Center for Pulmonary Hypertension at the Thoraxclinic, University Hospital Heidelberg, Heidelberg, 69126, Germany.|Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), Heidelberg, Germany.
Ekkehard
E
Grünig
Institute of Human Genetics, Heidelberg University, Im Neuenheimer Feld 366, 69120, Heidelberg, Germany. katrin.hinderhofer@med.uni-heidelberg.de.
Katrin
K
Hinderhofer
D000328:Adult; D000369:Aged, 80 and over; D062186:Arterial Pressure / Q000235:genetics*; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D040941:Heredity; D006801:Humans; D006976:Hypertension, Pulmonary / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D019683:Penetrance; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011651:Pulmonary Artery / Q000503:physiopathology*; D055815:Young Adult
C529271:EIF2AK4 protein, human; D017346:Protein Serine-Threonine Kinases; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II
Hereditary pulmonary arterial hypertension; Next generation sequencing; Pulmonary veno-occlusive disease; Two-gene model