title: EIF2AK4 Mutations in Patients Diagnosed With Pulmonary Arterial Hypertension.
abstract: Differentiating pulmonary venoocclusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH) from idiopathic pulmonary arterial hypertension (IPAH) or heritable pulmonary arterial hypertension (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 was to describe the frequency of pathogenic EIF2AK4 mutations in patients diagnosed clinically with IPAH or HPAH.
  
  
  
  Sanger sequencing and deletion/duplication analysis were performed to detect mutations in the bone morphogenetic protein receptor type II (BMPR2) gene in 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, and 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%) patients with IPAH and 6 of 9 (66.7%) patients with HPAH. A novel homozygous EIF2AK4 mutation (c.257+4A>C) was identified 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 patients with IPAH had biallelic EIF2AK4 mutations.
  
  
  
  Pathogenic biallelic EIF2AK4 mutations are rarely identified in patients diagnosed with HPAH. Identification of pathogenic biallelic EIF2AK4 mutations can aid clinicians in differentiating HPAH from heritable PVOD or PCH.
authors.affiliation: ARUP Institute for Clinical and Experimental Pathology, ARUP Laboratories, Salt Lake City, UT; Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT; Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT.
authors.forename: D Hunter
authors.initials: DH
authors.lastname: Best
authors.affiliation: ARUP Institute for Clinical and Experimental Pathology, ARUP Laboratories, Salt Lake City, UT.
authors.forename: Kelli L
authors.initials: KL
authors.lastname: Sumner
authors.affiliation: Department of Medicine, Intermountain Medical Center, Murray, UT; Department of Internal Medicine, University of Utah, Salt Lake City, UT.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Smith
authors.affiliation: ARUP Institute for Clinical and Experimental Pathology, ARUP Laboratories, Salt Lake City, UT.
authors.forename: Kristy
authors.initials: K
authors.lastname: Damjanovich-Colmenares
authors.affiliation: Department of Medicine, Intermountain Medical Center, Murray, UT.
authors.forename: Ikue
authors.initials: I
authors.lastname: Nakayama
authors.affiliation: Department of Medicine, Intermountain Medical Center, Murray, UT; Department of Internal Medicine, University of Utah, Salt Lake City, UT.
authors.forename: Lynette M
authors.initials: LM
authors.lastname: Brown
authors.affiliation: ARUP Institute for Clinical and Experimental Pathology, ARUP Laboratories, Salt Lake City, UT.
authors.forename: Youna
authors.initials: Y
authors.lastname: Ha
authors.affiliation: ARUP Institute for Clinical and Experimental Pathology, ARUP Laboratories, Salt Lake City, UT.
authors.forename: Eleri
authors.initials: E
authors.lastname: Paul
authors.affiliation: ARUP Institute for Clinical and Experimental Pathology, ARUP Laboratories, Salt Lake City, UT.
authors.forename: Ashley
authors.initials: A
authors.lastname: Morris
authors.affiliation: ARUP Institute for Clinical and Experimental Pathology, ARUP Laboratories, Salt Lake City, UT.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Jama
authors.affiliation: Department of Medicine, Intermountain Medical Center, Murray, UT; Department of Internal Medicine, University of Utah, Salt Lake City, UT.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Dodson
authors.affiliation: ARUP Institute for Clinical and Experimental Pathology, ARUP Laboratories, Salt Lake City, UT; Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT.
authors.forename: Pinar
authors.initials: P
authors.lastname: Bayrak-Toydemir
authors.affiliation: Department of Medicine, Intermountain Medical Center, Murray, UT; Department of Internal Medicine, University of Utah, Salt Lake City, UT. Electronic address: greg.elliott@imail.org.
authors.forename: C Gregory
authors.initials: CG
authors.lastname: Elliott
mesh_terms: D000328:Adult; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009656:North America; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*
chemical_list: C529271:EIF2AK4 protein, human; D017346:Protein Serine-Threonine Kinases; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II
keywords: genetics; pulmonary capillary hemangiomatosis; pulmonary hypertension; pulmonary venoocclusive disease