Taijun Hana1, Hideki Ogiwara2, Ohsuke Migita3,4, Kazuhiko Nakabayashi3, Kenichiro Hata3, Nobuhito Morota2,5. 1. Department of Neurosurgery, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-Ku, Tokyo, 157-8535, Japan. thana-tky@umin.ac.jp. 2. Department of Neurosurgery, National Center for Child Health and Development, 2-10-1 Okura, Setagaya-Ku, Tokyo, 157-8535, Japan. 3. Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-Ku, Tokyo, 157-8535, Japan. 4. Department of Pediatrics, St. Marianna University School of Medicine, 2-16-1, Sugao, Miyamae-Ku, Kawasaki, Kanagawa, 216-8511, Japan. 5. Department of Neurosurgery, Kitasato University Hospital, 1-15-1 Kitasato, Minami-Ku, Sagamihara, Kanagawa, 252-0374, Japan.
Abstract
PURPOSE: Despite numerous studies, the etiology of spinal extradural arachnoid cyst (SEDAC), a lesion associated with neurological symptoms, remains unknown. In this genomic twin study, we investigated the genetic etiology of SEDACs. METHODS: The subjects were identical twins who developed notably similar SEDACs at the same vertebral level. Accordingly, we performed whole-exome sequencing analyses of genomic material from the twins and their parents using a next-generation sequencer. Additionally, we determined their detailed family history and analyzed the family pedigree. RESULTS: The pedigree analysis suggested the potential presence of SEDACs in certain family members, indicating a genetic disease. Sequenced data were analyzed and filtered using a purpose-built algorithm, leading to the identification of 155 novel single-nucleotide polymorphisms (SNPs), of which 118 encoded missense or nonsense variants. A functional analysis of the proteins encoded by these SNP alleles revealed strong enrichment for the fibronectin type III (FN3) protein domain (q = 0.00576). Specifically, the data indicated that a missense variant affecting the FN3 protein domain of fibronectin 1 (FN1, p.P969S) can be the causal mutation underlying the SEDACs. CONCLUSION: The data suggest that deleterious mutations in fibronectin-related genes may cause SEDACs. In particular, it was suspected that a variant of FN1 may be the cause of the SEDACs in the twin cases studied herein. Detailed studies with a larger number of cases are needed.
PURPOSE: Despite numerous studies, the etiology of spinal extradural arachnoid cyst (SEDAC), a lesion associated with neurological symptoms, remains unknown. In this genomic twin study, we investigated the genetic etiology of SEDACs. METHODS: The subjects were identical twins who developed notably similar SEDACs at the same vertebral level. Accordingly, we performed whole-exome sequencing analyses of genomic material from the twins and their parents using a next-generation sequencer. Additionally, we determined their detailed family history and analyzed the family pedigree. RESULTS: The pedigree analysis suggested the potential presence of SEDACs in certain family members, indicating a genetic disease. Sequenced data were analyzed and filtered using a purpose-built algorithm, leading to the identification of 155 novel single-nucleotide polymorphisms (SNPs), of which 118 encoded missense or nonsense variants. A functional analysis of the proteins encoded by these SNP alleles revealed strong enrichment for the fibronectin type III (FN3) protein domain (q = 0.00576). Specifically, the data indicated that a missense variant affecting the FN3 protein domain of fibronectin 1 (FN1, p.P969S) can be the causal mutation underlying the SEDACs. CONCLUSION: The data suggest that deleterious mutations in fibronectin-related genes may cause SEDACs. In particular, it was suspected that a variant of FN1 may be the cause of the SEDACs in the twin cases studied herein. Detailed studies with a larger number of cases are needed.
Authors: Aaron McKenna; Matthew Hanna; Eric Banks; Andrey Sivachenko; Kristian Cibulskis; Andrew Kernytsky; Kiran Garimella; David Altshuler; Stacey Gabriel; Mark Daly; Mark A DePristo Journal: Genome Res Date: 2010-07-19 Impact factor: 9.043
Authors: John F Burke; Jayesh P Thawani; Ian Berger; Nikhil R Nayak; James H Stephen; Tunde Farkas; Hovik John Aschyan; John Pierce; Suhail Kanchwala; Donlin M Long; William C Welch Journal: J Neurosurg Spine Date: 2016-01-08