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Exome sequencing identifies a novel intronic mutation in ENG that causes recurrence of pulmonary arteriovenous malformations

  • Author Footnotes
    1 The first three authors contributed equally to this work.
    ,
    Author Footnotes
    2 The two corresponding authors contributed equally to this work.
    Naoki Saji
    Correspondence
    Correspondence to: N. Saji, Department of Stroke Medicine, Kawasaki Medical School, 577 Matsushima, Kurashiki City, Okayama, 701-0192, Japan. Tel.: +81 86 462 1111; fax; +81 86 462 1199.
    Footnotes
    1 The first three authors contributed equally to this work.
    2 The two corresponding authors contributed equally to this work.
    Affiliations
    Department of Stroke Medicine, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan
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  • Author Footnotes
    1 The first three authors contributed equally to this work.
    ,
    Author Footnotes
    2 The two corresponding authors contributed equally to this work.
    Toshitaka Kawarai
    Correspondence
    Correspondence to: T. Kawarai, Department of Clinical Neuroscience, Institute of Health Biosciences, Graduate School of Medicine, University of Tokushima, 3-18-15, Kuramoto-cho, Tokushima City, 770-0042, Japan. Tel.: +81 88 633 7207; fax: +81 88 633 7208.
    Footnotes
    1 The first three authors contributed equally to this work.
    2 The two corresponding authors contributed equally to this work.
    Affiliations
    Department of Clinical Neuroscience, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503, Japan
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  • Author Footnotes
    1 The first three authors contributed equally to this work.
    Ryosuke Miyamoto
    Footnotes
    1 The first three authors contributed equally to this work.
    Affiliations
    Department of Clinical Neuroscience, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503, Japan
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  • Takahiro Sato
    Affiliations
    Department of Stroke Medicine, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan
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  • Hiroyuki Morino
    Affiliations
    Department of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
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  • Antonio Orlacchio
    Affiliations
    Laboratorio di Neurogenetica, CERC-IRCCS Santa Lucia, Rome, Italy

    Dipartimento di Medicina dei Sistemi, Università di Roma “Tor Vergata”, Rome, Italy
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  • Ryosuke Oki
    Affiliations
    Department of Clinical Neuroscience, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503, Japan
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  • Kazumi Kimura
    Affiliations
    Department of Stroke Medicine, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan
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  • Ryuji Kaji
    Affiliations
    Department of Clinical Neuroscience, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503, Japan
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  • Author Footnotes
    1 The first three authors contributed equally to this work.
    2 The two corresponding authors contributed equally to this work.
Published:April 01, 2015DOI:https://doi.org/10.1016/j.jns.2015.02.007

      Abstract

      Hereditary hemorrhagic telangiectasia (HHT) occasionally can be discovered in patients with cerebrovascular disease. Pulmonary arteriovenous malformation (PAVM) is one of the complications in HHT and occasionally is causative for life-threatening embolic stroke. Several genetic defects have been reported in patients with HHT. The broad spectrum of phenotype and intrafamilial phenotype variations, including age-at-onset of vascular events, often make an early diagnosis difficult. We present here a Japanese family with a novel intronic heterozygous mutation of ENG, which was identified using whole exome sequencing (WES). The intronic mutation, IVS3 + 4delAGTG, results in in-frame deletion of exon 3 and would produce a shorter ENG protein lacking the extracellular forty-seven amino acid sequences, which is located within the orphan domain. Our findings highlight the importance of the domain for the downstream signaling pathway of transforming growth factor-beta and bone morphogenesis protein superfamily receptors. Considering the phenotype variations and the available treatment for vascular complications, an early diagnosis using genetic testing, including WES, should be considered for individuals at risk of HHT.

      Abbreviations:

      AD (autosomal dominant), AVM (arteriovenous malformation), CT (computed tomography), ENG (endoglin), ESS (epistaxis severity score), HHT (hereditary hemorrhagic telangiectasia), MRI (magnetic resonance imaging), NGS (next-generation sequencing), PAVM (pulmonary arteriovenous malformation), WES (Whole exome sequencing)

      Keywords

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