دورية أكاديمية
Phenotypic characterisation of EIF2AK4 mutation carriers in a large cohort of patients diagnosed clinically with pulmonary arterial hypertension
| العنوان: | Phenotypic characterisation of EIF2AK4 mutation carriers in a large cohort of patients diagnosed clinically with pulmonary arterial hypertension |
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| المؤلفون: | Hadinnapola, C, Bleda, M, Haimel, M, Screaton, N, Swift, AJ, Dorfmüller, P, Preston, SD, Southwood, M, Hernandez-Sanchez, J, Martin, J, Treacy, C, Yates, K, Bogaard, H, Church, C, Coghlan, G, Condliffe, R, Corris, PA, Gibbs, SR, Girerd, B, Holden, S, Humbert, M, Kiely, DG, Lawrie, A, Machado, RD, MacKenzie Ross, R, Moledina, S, Montani, D, Newnham, M, Peacock, AJ, Pepke-Zaba, J, Rayner-Matthews, PJ, Shamardina, O, Soubrier, F, Southgate, L, Suntharalingam, J, Toshner, MR, Trembath, RC, Vonk Noordegraaf, A, Wilkins, MR, Wort, SJ, Wharton, J, Gräf, S, Morrell, NW, NIHR BioResource - Rare Diseases Consortium & UK National Cohort Study of Idiopathic and Heritable PAH |
| المساهمون: | British Heart Foundation |
| المصدر: | 2033 ; 2022 |
| بيانات النشر: | American Heart Association |
| سنة النشر: | 2017 |
| المجموعة: | Imperial College London: Spiral |
| مصطلحات موضوعية: | EIF2AK4, genetics, human, prognosis, pulmonary hypertension, pulmonary veno-occlusive disease, Science & Technology, Life Sciences & Biomedicine, Cardiac & Cardiovascular Systems, Peripheral Vascular Disease, Cardiovascular System & Cardiology, hypertension, pulmonary, mutation, VENOOCCLUSIVE-DISEASE, DIFFUSION CAPACITY, BMPR2, CT, Adult, Aged, Arterial Pressure, Bone Morphogenetic Protein Receptors, Type II, DNA Mutational Analysis, Europe, Female, Gene Frequency, Genetic Association Studies, Genetic Predisposition to Disease, Heredity |
| الوصف: | Background -Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) are described in pulmonary veno-occlusive disease and pulmonary capillary haemangiomatosis (PVOD/PCH). Here, we determined the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. Methods -Whole genome sequencing was performed on DNA from patients with idiopathic and heritable PAH, as well as PVOD/PCH recruited to the NIHR 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 CADD, PolyPhen-2 and SIFT predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. Results -Eight hundred and sixty-four patients with idiopathic or heritable PAH and 16 with PVOD/PCH 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 PVOD/PCH. 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 [IQR: 30 - 35] % predicted) and younger age at diagnosis (29 [23 - 38] years) as well as more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest, compared to PAH patients without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. PAH patients with biallelic EIF2AK4 mutations had a shorter survival. Conclusions -Biallelic EIF2AK4 mutations are found in patients classified ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 0009-7322 |
| العلاقة: | Circulation; http://hdl.handle.net/10044/1/51826Test; RG68204 13/EE/0203 A092860 |
| DOI: | 10.1161/CIRCULATIONAHA.117.028351 |
| الإتاحة: | https://doi.org/10.1161/CIRCULATIONAHA.117.028351Test http://hdl.handle.net/10044/1/51826Test |
| حقوق: | © 2017 Circulation is published on behalf of the American Heart Association, Inc., by Wolters Kluwer. This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0Test/), which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited. |
| رقم الانضمام: | edsbas.BC8A386C |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 00097322 |
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| DOI: | 10.1161/CIRCULATIONAHA.117.028351 |