Identification of a New Intronic BMPR2-Mutation and Early Diagnosis of Heritable Pulmonary Arterial Hypertension in a Large Family with Mean Clinical Follow-Up of 12 Years

Hinderhofer, Katrin; Fischer, Christine; Pfarr, Nicole; Szamalek-Hoegel, Justyna; Lichtblau, Mona; Nagel, Christian; Egenlauf, Benjamin; Ehlken, Nicola; Grünig, Ekkehard

doi:10.1371/journal.pone.0091374

Cited by 25 publications

(23 citation statements)

References 37 publications

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“…In contrast, BMPR2 mutations occur in up to 85 % of familial cases and are autosomal dominantly inherited [7, 8]. However, many BMPR2 gene carriers have no clinical symptoms and do not develop manifest PH even during a more than 10 year follow-up period [22]. Hence, the family described here provides an explanation for the decreased penetrance and suggests an autosomal dominantly contribution of EIF2AK4 to disease manifestation.…”

Section: Discussionmentioning

confidence: 96%

“…Clinical procedures consisted of recording the family and medical history, physical examination, laboratory parameters including N-type pro brain natriuretic peptide (NT-proBNP), 12-lead electrocardiogram, lung function test, arterial blood gases, 6-min walking distance, echocardiography, stress-Dopplerechocardiography and cardiopulmonary exercise testing as described previously [22]. High resolution computer tomography of the lung was conducted to exclude pulmonary veno-occlusive disease.…”

Section: Methodsmentioning

confidence: 99%

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EIF2AK4 mutation as “second hit” in hereditary pulmonary arterial hypertension

et al. 2016

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BackgroundMutations in the eukaryotic translation initiation factor 2α kinase 4 (EIF2AK4) gene have recently been identified in recessively inherited veno-occlusive disease. In this study we assessed if EIF2AK4 mutations occur also in a family with autosomal dominantly inherited pulmonary arterial hypertension (HPAH) and incomplete penetrance of bone morphogenic protein receptor 2 (BMPR2) mutations.MethodsClinical examinations in a family with 10 members included physical examination, electrocardiogram, (stress)-echocardiography and lung function. Manifest PAH was confirmed by right heart catheterisation in three affected subjects. Genetic analysis was performed using a new PAH-specific gene panel analysis with next generation sequencing of all known PAH and further candidate genes. Identified variants were confirmed by Sanger sequencing.ResultsAll living family members with manifest HPAH carried two pathogenic heterozygous mutations: a frame shift mutation in the BMPR2 gene and a novel splice site mutation in the EIF2AK4 gene. Two family members who carried the BMPR2 mutation only did not develop manifest HPAH.ConclusionsThis is the first study suggesting that EIF2AK4 can also contribute to autosomal dominantly inherited HPAH. Up to now it has only been identified in a recessive form of HPAH. Only those family members with a co-occurrence of two mutations developed manifest HPAH. Thus, the EIF2AK4 and BMRPR2 mutations support the “second hit” hypothesis explaining the variable penetrance of HPAH in this family. Hence, the assessment of all known PAH genes in families with a known mutation might assist in predictions about the clinical manifestation in so far non-affected mutation carriers.

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Section: Discussionmentioning

confidence: 96%

Section: Methodsmentioning

confidence: 99%

EIF2AK4 mutation as “second hit” in hereditary pulmonary arterial hypertension

et al. 2016

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“…A recent report by Hinderhofer et al. () has also identified an intronic mutation of BMPR2 that leads to aberrant splicing due to an insertion of an intronic Alu element 26 bp upstream from exon 6. This points to a potential role for other intronic variants or regulatory elements such as intra‐ or intergenic enhancer and repressor motifs in the pathogenesis of PAH.…”

Section: Future Prospectsmentioning

confidence: 99%

Pulmonary Arterial Hypertension: A Current Perspective on Established and Emerging Molecular Genetic Defects

et al. 2015

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Pulmonary arterial hypertension (PAH) is an often fatal disorder resulting from several causes including heterogeneous genetic defects. While mutations in the bone morphogenetic protein receptor type II (BMPR2) gene are the single most common causal factor for hereditary cases, pathogenic mutations have been observed in approximately 25% of idiopathic PAH patients without a prior family history of disease. Additional defects of the transforming growth factor beta (TGF-β) pathway have been implicated in disease pathogenesis. Specifically, studies have confirmed activin A receptor type II-like 1 (ACVRL1), endoglin (ENG) and members of the SMAD family as contributing to PAH both with and without associated clinical phenotypes. Most recently, next-generation sequencing has identified novel, rare genetic variation implicated in the PAH disease spectrum. Of importance, several identified genetic factors converge on related pathways and provide significant insight into the development, maintenance and pathogenetic transformation of the pulmonary vascular bed. Together, these analyses represent the largest comprehensive compilation of BMPR2 and associated genetic risk factors for PAH, comprising known and novel variation. Additionally, with the inclusion of an allelic series of locus-specific variation in BMPR2, these data provide a key resource in data interpretation and development of contemporary therapeutic and diagnostic tools.

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“…[33,49]. Die regelmäßige klinische Untersuchung Betroffener und zumindest deren erstgradiger Familienmitglieder mittels Echokardiographie können beitragen, die Erkrankung bei Betroffenen zu einem früheren Zeitpunkt zu diagnostizieren [34]. Die Identifikation genetischer Mutationen kann helfen, Familienmitgliedern die diese Mutation nicht haben, weitere Kontrolluntersuchungen zu ersparen [48].…”

Section: Genetik Der Pah ▼unclassified

“…B. Herzultraschall in Ruhe und unter Belastung, um eine PAH im Anfangsstadium frühestmög-lich zu erkennen[34]. Es sollte jedoch beachtet werden, dass durch die variable Penetranz eine Manifestation der Krankheit nicht zuverlässig vorhergesagt werden kann.…”

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