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102 Exome Sequencing Identifies Novel Molecular Determinants of Human Congenital Hydrocephalus

Neurosurgery, 2017-09, Vol.64 (CN_suppl_1), p.220-220 [Peer Reviewed Journal]

Copyright © 2017 by the Congress of Neurological Surgeons 2017 ;Copyright © by the Congress of Neurological Surgeons ;Copyright © 2017 Congress of Neurological Surgeons ;ISSN: 0148-396X ;EISSN: 1524-4040 ;DOI: 10.1093/neuros/nyx417.102

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  • Title:
    102 Exome Sequencing Identifies Novel Molecular Determinants of Human Congenital Hydrocephalus
  • Author: Furey, Charuta Gavankar ; Choi, Jungmin ; Duran, Daniel ; Timberlake, Andrew T ; Zeng, Xue ; Nelson-Williams, Carol ; Khanna, Arjun ; Iskandar, Bermans ; Butler, William ; Heuer, Gregory George ; Bayri, Yasar ; Sahin, Yener ; Limbrick, David D ; Warf, Benjamin C ; Duncan, Charles C ; DiLuna, Michael L ; Gunel, Murat ; Lifton, Richard P ; Kahle, Kristopher Thomas
  • Subjects: Congenital diseases ; Genes ; Hydrocephalus ; Mutation
  • Is Part Of: Neurosurgery, 2017-09, Vol.64 (CN_suppl_1), p.220-220
  • Description: Abstract INTRODUCTION Congenital hydrocephalus (CH), with an estimated prevalence of 1 in 1000 births, is the most common disease treated by pediatric neurosurgeons, and exerts a tremendous burden on the United States health care budget, consuming over $2 billion annually. Paradoxically, CH treatments remain inadequate, crude, and primarily symptomatic, comprised largely of surgical shunts riddled with infectious and mechanical complications. Despite evidence that genetic factors play a major role in the pathogenesis of CH an estimated 40% of human CH has a genetic etiology our knowledge of specific CH-causing mutations and their pathogenic mechanisms remains primitive. Understanding critical genetic drivers underlying human CH holds promise for the development of targeted therapies. However, traditional genetic approaches have been limited in their ability to identify causative CH genes because kindreds are rare, small in size, or appear to have sporadic inheritance patterns. Next-generation sequencing, and specifically whole exome sequencing (WES), can overcome these barriers to gene discovery. METHODS We performed whole-exome sequencing on DNA isolated from 130 patient-parent trios (affected patient and unaffected parents) and an additional 57 probands for a total of 187 CH patients with non-L1CAM primary CH. Exome-sequencing data from these 447 individuals was then analyzed to identify rare, de novo and transmitted mutations contributing to CH, and candidate mutations were subsequently confirmed by Sanger sequencing. RESULTS >Exome sequencing identified multiple novel and recurrent de novo and transmitted loss-of function gene mutations enriched in neurodevelopmental and ciliogenesis pathways. Binomial and case-control analyses confirmed exome-wide statistical significance of candidate genes, and functional modeling in Xenopus established gene causality. CONCLUSION These findings reveal novel disease-causing mutations in human CH, thereby providing new opportunities for improved prognostic assessment and non-invasive therapies.
  • Publisher: Oxford: Oxford University Press
  • Language: English
  • Identifier: ISSN: 0148-396X
    EISSN: 1524-4040
    DOI: 10.1093/neuros/nyx417.102
  • Source: AUTh Library subscriptions: ProQuest Central
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