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Original Research: Pulmonary Vascular Disease |

EIF2AK4 Mutations in Patients Diagnosed With Pulmonary Arterial Hypertension

D. Hunter Best, PhD; Kelli L. Sumner, BS; Benjamin P. Smith, MD; Kristy Damjanovich-Colmenares, BS; Ikue Nakayama, MD; Lynette M. Brown, MD, PhD; Youna Ha, BS; Eleri Paul, MLS (ASCP); Ashley Morris, MLS (ASCP); Mohamed A. Jama, MS, MB (ASCP); Mark W. Dodson, MD, PhD; Pinar Bayrak-Toydemir, MD, PhD; C. Gregory Elliott, MD, FCCP
Author and Funding Information

Dr Best and Ms Sumner contributed equally to this manuscript.

FUNDING/SUPPORT: The authors have reported to CHEST that no funding was received for this study.

aARUP Institute for Clinical and Experimental Pathology, ARUP Laboratories, Salt Lake City, UT

bDepartment of Pathology, University of Utah School of Medicine, Salt Lake City, UT

cDepartment of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT

dDepartment of Medicine, Intermountain Medical Center, Murray, UT

eDepartment of Internal Medicine, University of Utah, Salt Lake City, UT

CORRESPONDENCE TO: C. Gregory Elliott, MD, FCCP, Department of Medicine, Intermountain Medical Center, 5121 S Cottonwood, #307, Murray, UT 84107


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2017;151(4):821-828. doi:10.1016/j.chest.2016.11.014
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Background  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.

Methods  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.

Results  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.

Conclusions  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.

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