Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension.
Abstract | BACKGROUND: METHODS: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource- Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of <1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. RESULTS: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (Kco; 33% [interquartile range, 30%-35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23-38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. CONCLUSIONS: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low Kco and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation.
|
Authors | Charaka Hadinnapola, Marta Bleda, Matthias Haimel, Nicholas Screaton, Andrew Swift, Peter Dorfmüller, Stephen D Preston, Mark Southwood, Jules Hernandez-Sanchez, Jennifer Martin, Carmen Treacy, Katherine Yates, Harm Bogaard, Colin Church, Gerry Coghlan, Robin Condliffe, Paul A Corris, Simon Gibbs, Barbara Girerd, Simon Holden, Marc Humbert, David G Kiely, Allan Lawrie, Rajiv Machado, Robert MacKenzie Ross, Shahin Moledina, David Montani, Michael Newnham, Andrew Peacock, Joanna Pepke-Zaba, Paula Rayner-Matthews, Olga Shamardina, Florent Soubrier, Laura Southgate, Jay Suntharalingam, Mark Toshner, Richard Trembath, Anton Vonk Noordegraaf, Martin R Wilkins, Stephen J Wort, John Wharton, NIHR BioResource–Rare Diseases Consortium; UK National Cohort Study of Idiopathic and Heritable PAH, Stefan Gräf, Nicholas W Morrell |
Journal | Circulation
(Circulation)
Vol. 136
Issue 21
Pg. 2022-2033
(11 21 2017)
ISSN: 1524-4539 [Electronic] United States |
PMID | 28972005
(Publication Type: Journal Article, Multicenter Study)
|
Copyright | © 2017 The Authors. |
Chemical References |
- EIF2AK4 protein, human
- Protein Serine-Threonine Kinases
- BMPR2 protein, human
- Bone Morphogenetic Protein Receptors, Type II
|
Topics |
- Adult
- Aged
- Arterial Pressure
(genetics)
- Bone Morphogenetic Protein Receptors, Type II
(genetics)
- DNA Mutational Analysis
- Europe
- Female
- Gene Frequency
- Genetic Association Studies
- Genetic Predisposition to Disease
- Heredity
- Humans
- Hypertension, Pulmonary
(diagnosis, enzymology, genetics, physiopathology)
- Male
- Middle Aged
- Mutation
- Pedigree
- Phenotype
- Predictive Value of Tests
- Prospective Studies
- Protein Serine-Threonine Kinases
(genetics)
- Pulmonary Artery
(physiopathology)
- Retrospective Studies
- Risk Factors
- Tomography, X-Ray Computed
- Young Adult
|
|
Join CureHunter, for free Research Interface BASIC access!
Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease.
Find out why thousands of doctors, pharma researchers and patient activists
around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!
|