EIF2AK4 Mutations in Patients Diagnosed With Pulmonary Arterial Hypertension

Best, D. Hunter; Sumner, Kelli; Smith, B. L.; Damjanovich-Colmenares, Kristy; Nakayama, Ikue; Brown, Lynette M.; Ha, Youna; Paul, Eleri; Morris, Ashley; Jama, Mohamed; Dodson, Mark K.; Bayrak-Toydemir, Pınar; Elliott, C. Gregory

doi:10.1016/j.chest.2016.11.014

Cited by 60 publications

(60 citation statements)

References 24 publications

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“…indicating that variations in this gene constitute a rare molecular trigger for PAH 60 . Further validation for a pathogenic role of EIF2AK4 mutations in patients clinically diagnosed with PAH was provided by a study that identified nine patients (out of 864) with biallelic EIF2AK4 mutations 61 .…”

Section: [H2] Autosomal Recessive Pah Subtypesmentioning

confidence: 99%

Molecular genetic framework underlying pulmonary arterial hypertension

et al. 2019

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| Pulmonary arterial hypertension (PAH) is a rare, progressive disorder typified by occlusion of the pulmonary arterioles owing to endothelial dysfunction and uncontrolled proliferation of pulmonary artery smooth muscle cells and fibroblasts. Vascular occlusion can lead to increased pressure in the pulmonary arteries, often resulting in right ventricular failure with shortness of breath and syncope. Since the identification of BMPR2, which encodes a receptor in the transforming growth factor-β superfamily, the development of highthroughput sequencing approaches to identify novel causal genes has substantially advanced our understanding of the molecular genetics of PAH. In the past 6 years, additional pathways involved in PAH susceptibility have been described through the identification of deleterious genetic variants in potassium channels (KCNK3 and ABCC8) and transcription factors (TBX4 and SOX17), among others. Although familial PAH most often has an autosomal dominant pattern of inheritance, cases of incomplete penetrance and evidence of genetic heterogeneity support a model of PAH as a Mendelian disorder with complex disease features. In this Review, we outline the latest advances in the detection of rare and common genetic variants underlying PAH susceptibility and disease progression. These findings have clinical implications on lung vascular function and can help to identify mechanistic pathways amenable to pharmacological intervention. P ag e | 2

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Section: [H2] Autosomal Recessive Pah Subtypesmentioning

confidence: 99%

Molecular genetic framework underlying pulmonary arterial hypertension

et al. 2019

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“…Bi-allelic mutations of EIF2AK4 were identified in 5 PVOD/PCH patients and in 9 IPAH patients (1%). Interestingly, EIF2AK4 positive IPAH patients, investigated both by Best et al [15] and by Hadinnapola et al [16], exhibited clinical symptoms that might be indicative of PVOD/PCH.…”

Section: Genetic Alterations In Pvod/pchmentioning

confidence: 99%

“…Best et al [15] found bi-allelic EIF2AK4 mutations in 1 out of 9 hereditary PAH (hPAH) patients, and none of 72 IPAH patients.…”

Section: Genetic Alterations In Pvod/pchmentioning

confidence: 99%

Pulmonary Veno-Occlusive Disease: Pathogenesis, Risk Factors, Clinical Features and Diagnostic Algorithm—State of the Art

Szturmowicz¹,

Kacprzak²,

Szołkowska³

et al. 2018

Advances in Respiratory Medicine

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Pulmonary veno-occlusive disease (PVOD) and pulmonary capillary haemangiomatosis (PCH) are rare disorders, with the estimated prevalence of less than 1 case per million inhabitants. The vascular pathology in PVOD/PCH involves pre-septal and septal veins, alveolar capillaries and small pulmonary arteries. According to the ERS/ESC classification of pulmonary hypertension (PH) from 2015, PVOD/PCH have been included in the subgroup 1' of pulmonary arterial hypertension (PAH). Recent data indicate, however, the possibility of PVOD/PCH pathology in the patients diagnosed in the group 1. The problem may concern PAH associated with scleroderma, drug-induced PAH, PAH due to HIV infection and up to 10% of patients with idiopathic PAH (IPAH). Recently, bi-allelic EIF2AK4 mutations were found in the cases with heritable form of PVOD/PCH and in about 9% of sporadic cases. Moreover, an association between occupational exposure to organic solvents and PVOD/PCH was proved. The present review is an attempt to summarise the current data on pathogenesis, risk factors, clinical features and diagnostic algorithm for PVOD/PCH.

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“…We sequence BMPR2, ACVRL1, endoglin, CAV1, KCNK3, SMAD9, TBX4 and EIF2AK4 genes for all patients, although there is no biological basis for sequencing EIF2AK4 gene in patients with heritable PAH with a clearly autosomal dominant pattern of inheritance, but this does not represent any additional cost. Moreover, when the inheritance pattern may be either autosomal dominant or autosomal recessive, this technique could enable clarification or confirmation of the diagnosis of PAH or PVOD/PCH (as demonstrated recently by BEST et al [44]). An identified mutation is then confirmed using Sanger sequencing.…”

Section: Genetic Counsellingmentioning

confidence: 99%

“…Distinguishing PVOD/PCH from PAH on clinical grounds can be challenging, since physical and haemodynamic findings are broadly similar. However, the presence of EIF2AK4 mutations could help to diagnose PVOD/PCH in patients with precapillary pulmonary hypertension [44]. Histological examination of the lungs from bi-allelic EIF2AK4 mutations carriers revealed extensive occlusion of pulmonary veins by fibrous tissue, intimal thickening of venules and small veins in the lobular septae and localised capillary proliferation.…”

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confidence: 99%

Heritable pulmonary hypertension: from bench to bedside

et al. 2017

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Mutations in the BMPR2 gene, and more rarely in ACVRL1, endoglin, caveolin-1, KCNK3 and TBX4 genes predispose to heritable pulmonary arterial hypertension, an autosomal dominant disease with incomplete penetrance. Bi-allelic mutations in the EIF2AK4 gene predispose to heritable pulmonary veno-occlusive disease/pulmonary capillary haemangiomatosis, an autosomal recessive disease with an unknown penetrance.In France, the national pulmonary hypertension referral centre offers genetic counselling and testing to adults and children. Predictive testing is also proposed to adult relatives at risk of carrying a predisposing mutation. In that context, we offer all asymptomatic BMPR2 mutation carriers a programme to detect pulmonary arterial hypertension at an early phase, as recommended by the

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EIF2AK4 Mutations in Patients Diagnosed With Pulmonary Arterial Hypertension

Cited by 60 publications

References 24 publications

Molecular genetic framework underlying pulmonary arterial hypertension

Molecular genetic framework underlying pulmonary arterial hypertension

Pulmonary Veno-Occlusive Disease: Pathogenesis, Risk Factors, Clinical Features and Diagnostic Algorithm—State of the Art

Heritable pulmonary hypertension: from bench to bedside

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