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Original Research |

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, MACP, FCCP
Author and Funding Information

Disclosures: DHB, BPS, KD-C, IN, YH, AM, MAJ, MWD, and PB-T have nothing to disclose. KLS and EP are employed by ARUP Laboratories. LMB and CGE are employed by Intermountain Healthcare. Intermountain Healthcare may receive revenue related to licensing of genetic markers and has received grants from Actelion, Bayer, Bellerophon, and Lung Biotechnology. CGE has served as a consultant for Actelion, Bayer, Ikaria and Bellerophon.

1ARUP Institute for Clinical and Experimental Pathology, ARUP Laboratories, Salt Lake City, UT

2Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT

3Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT

4Department of Medicine, Intermountain Medical Center, Murray, UT

5Department of Internal Medicine University of Utah, Salt Lake City, UT

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


Copyright 2016, . All Rights Reserved.


Chest. 2016. doi:10.1016/j.chest.2016.11.014
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Abstract

Background  Differentiating pulmonary veno-occlusive disease (PVOD) and pulmonary capillary hemangiomatosis (PCH) from idiopathic or heritable pulmonary arterial hypertension (IPAH and 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 is to describe the frequency of pathogenic EIF2AK4 mutations in patients diagnosed clinically with IPAH or HPAH.

Methods  We performed Sanger sequencing and deletion/duplication analysis to detect mutations in the BMPR2 gene on 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, 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%) IPAH patients and 6 of 9 (66.7%) HPAH patients. We identified a novel homozygous EIF2AK4 mutation (c.257+4A>C) 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 IPAH patients had bi-allelic EIF2AK4 mutations.

Conclusions  Pathogenic bi-allelic EIF2AK4 mutations are identified rarely in patients diagnosed with HPAH. Identification of pathogenic bi-allelic EIF2AK4 mutations can aid clinicians in differentiating HPAH from heritable PVOD or PCH.


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