title: Exome sequencing identifies a novel intronic mutation in ENG that causes recurrence of pulmonary arteriovenous malformations.
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.
authors: Department of Stroke Medicine, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan. Electronic address: sajink@me.com.
authors: Naoki
authors: N
authors: Saji
authors: Department of Clinical Neuroscience, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503, Japan. Electronic address: tkawarai@tokushima-u.ac.jp.
authors: Toshitaka
authors: T
authors: Kawarai
authors: Department of Clinical Neuroscience, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503, Japan. Electronic address: ninigii@gmail.com.
authors: Ryosuke
authors: R
authors: Miyamoto
authors: Department of Stroke Medicine, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan. Electronic address: sato.takabee1987@gmail.com.
authors: Takahiro
authors: T
authors: Sato
authors: Department of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.. Electronic address: morino@hiroshima-u.ac.jp.
authors: Hiroyuki
authors: H
authors: Morino
authors: Laboratorio di Neurogenetica, CERC-IRCCS Santa Lucia, Rome, Italy; Dipartimento di Medicina dei Sistemi, Università di Roma "Tor Vergata", Rome, Italy. Electronic address: a.orlacchio@hsantalucia.it.
authors: Antonio
authors: A
authors: Orlacchio
authors: Department of Clinical Neuroscience, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503, Japan. Electronic address: okkey19840323@gmail.com.
authors: Ryosuke
authors: R
authors: Oki
authors: Department of Stroke Medicine, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan. Electronic address: k-kimura@nms.ac.jp.
authors: Kazumi
authors: K
authors: Kimura
authors: Department of Clinical Neuroscience, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8503, Japan. Electronic address: rkaji@tokushima-u.ac.jp.
authors: Ryuji
authors: R
authors: Kaji
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000235:genetics*; D001164:Arteriovenous Fistula / Q000209:etiology / Q000235:genetics*; D044466:Asian People; D000071063:Endoglin; D059472:Exome; D005260:Female; D016368:Frameshift Mutation; D006801:Humans; D007438:Introns; D008297:Male; D008875:Middle Aged; D011651:Pulmonary Artery / Q000002:abnormalities*; D011667:Pulmonary Veins / Q000002:abnormalities*; D011956:Receptors, Cell Surface / Q000235:genetics*; D012008:Recurrence; D017422:Sequence Analysis, DNA; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000150:complications / Q000235:genetics*
chemical_list: D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D011956:Receptors, Cell Surface
keywords: Aberrant transcript; Arteriovenous malformation; Endoglin; Hereditary hemorrhagic telangiectasia; Intronic mutation; Whole exome sequencing