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

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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.

Introduction

Hereditary hemorrhagic telangiectasia (HHT), also known as Osler–Weber–Rendu disease, is an autosomal dominantly inherited vascular disease. Salient clinical features include the presence of mucocutaneous telangiectasia and arteriovenous malformations (AVM) in visceral organs, primarily the lungs, brain and liver. Early treatment of pulmonary arteriovenous malformations (PAVM), through which paradoxical brain embolism mediates, would ameliorate prognosis for a patient with HHT. Combination of accurate diagnosis by genetic testing, early treatment of PAVM, and careful clinical follow-up is crucial for HHT patients. However, even with early treatment, recurrence of pulmonary arteriovenous malformations has been reported after successful surgical removal or embolization treatment [1]. To date, four genes have been identified, ENG (HHT1), ACVRL1 (HHT2), SMAD4 and GDF2 (HHT5). It has been demonstrated that HHT is caused by either mutations in these genes or other genes that modulate transforming growth factor-beta (TGF-β) signaling (e.g., bone morphogenetic proteins). Two loci have been reported by linkage studies in familial cases, HHT3 and HHT4 on the region of 5q31.3-q32 and 7p14, respectively, in which the causative genes remain unknown [2]. Elucidation of genetic mechanisms would further contribute to better understanding the molecular pathogenicity of vasculopathy and developing new therapeutic strategies in HHT. We present here a family with a novel intronic mutation in ENG, and demonstrate further evidence of allelic heterogeneity in ENG-HHT1.

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Ethics statement

The study was approved by the ethical review boards of the Kawasaki Medical Hospital and Tokushima University Hospital. All of the participants in this study gave written informed consent.

Subjects

The pedigree chart is illustrated in Fig. 1. There were three family members with a history of spontaneous and repeated epistaxis including the proband (Fig. 1: II-1, III-1 and III-2). Other members in this family presented as normal. All the living family members were examined by three experienced

Clinical features

The proband, a 61-year-old man, suddenly developed behavioral disorders and referred to the emergency unit in Kawasaki Medical Hospital. Physical examination demonstrated multiple telangiectasias on his lips, tongue, fingers, and earlobes (Fig. 1-B). Epistaxis from telangiectasias of the nasal mucosa was confirmed by flexible fiberscopic examination (Fig. 1-C). He had a history of repeated nasal bleeding since his late twenties. ESS-HTT of 1.92, categorized as mild, was given at admission.

Discussion

To date, more than 27 ENG mutations have been reported in hereditary hemorrhagic telangiectasia (HHT), including nonsense, missense, frame shift, deletion and splicing mutations [3], [5], [6]. Haploinsufficiency is presumably a cardinal pathomechanism in HHT caused by mutant ENG. Missense mutant ENG proteins dimerize with themselves, as well as with wild-type ENG proteins, and localize in the rough endoplasmic reticulum (rER) or in the plasma membrane of the cells. When the mutant ENG proteins

Author contribution

Naoki Saji and Takahiro Sato: patient review and medical writing for content. Toshitaka Kawarai: genetic testing, sequencing of mutation, and manuscript preparation. Ryosuke Miyamoto, Hiroyuki Morino and Ryosuke Oki: genetic testing and bioinformatic analysis. Antonio Orlacchio, Kazumi Kimura and Ryuji Kaji: study supervision and coordination.

Conflict of interest

The authors report no conflicts of interest.

Acknowledgements

This work was supported by Grants-in-Aid from the Research Committee of CNS Degenerative Diseases of the Ministry of Health, Labour and Welfare of Japan (R.K.), the Japan Society for the Promotion of Science (JSPS KAKENHI Grant no. 26870765 to N.S. and no. 26461294 to T.K.), the Brain Science Foundation, Japan (Grant to T.K.), and Grant-in-Aid for Research on rare and intractable diseases, the Research Committee on Establishment of Novel Treatments for Amyotrophic Lateral Sclerosis from the

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1

The first three authors contributed equally to this work.

2

The two corresponding authors contributed equally to this work.

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