title: Biallelic mutations in human DCC cause developmental split-brain syndrome.
abstract: Motor, sensory, and integrative activities of the brain are coordinated by a series of midline-bridging neuronal commissures whose development is tightly regulated. Here we report a new human syndrome in which these commissures are widely disrupted, thus causing clinical manifestations of horizontal gaze palsy, scoliosis, and intellectual disability. Affected individuals were found to possess biallelic loss-of-function mutations in the gene encoding the axon-guidance receptor 'deleted in colorectal carcinoma' (DCC), which has been implicated in congenital mirror movements when it is mutated in the heterozygous state but whose biallelic loss-of-function human phenotype has not been reported. Structural MRI and diffusion tractography demonstrated broad disorganization of white-matter tracts throughout the human central nervous system (CNS), including loss of all commissural tracts at multiple levels of the neuraxis. Combined with data from animal models, these findings show that DCC is a master regulator of midline crossing and development of white-matter projections throughout the human CNS.
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts, USA.|Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.|Department of Paediatrics, KK Women's and Children's Hospital, Paediatric Academic Clinical Programme, Duke-NUS Medical School, Singapore.|Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts, USA.|Howard Hughes Medical Institute, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Saumya S
authors.initials: SS
authors.lastname: Jamuar
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts, USA.|Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.|Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Klaus
authors.initials: K
authors.lastname: Schmitz-Abe
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts, USA.|Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts, USA.|Howard Hughes Medical Institute, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Alissa M
authors.initials: AM
authors.lastname: D'Gama
authors.affiliation: Fetal-Neonatal Neuroimaging and Developmental Science Center, Division of Newborn Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Marie
authors.initials: M
authors.lastname: Drottar
authors.affiliation: Howard Hughes Medical Institute, Boston Children's Hospital, Boston, Massachusetts, USA.|Fetal-Neonatal Neuroimaging and Developmental Science Center, Division of Newborn Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.|Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Department of Ophthalmology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Wai-Man
authors.initials: WM
authors.lastname: Chan
authors.affiliation: Fetal-Neonatal Neuroimaging and Developmental Science Center, Division of Newborn Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.|Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Department of Ophthalmology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Maya
authors.initials: M
authors.lastname: Peeva
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts, USA.|Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts, USA.|Howard Hughes Medical Institute, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Servattalab
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts, USA.|Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts, USA.|Howard Hughes Medical Institute, Boston Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Anh-Thu N
authors.initials: AN
authors.lastname: Lam
authors.affiliation: Department of Neurology, Texas Scottish Rite Hospital for Children, Dallas, Texas, USA.|Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA.
authors.forename: Mauricio R
authors.initials: MR
authors.lastname: Delgado
authors.affiliation: Department of Neurology, Texas Scottish Rite Hospital for Children, Dallas, Texas, USA.
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Clegg
authors.affiliation: Department of Orthopedic Surgery, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
authors.forename: Zayed Al
authors.initials: ZA
authors.lastname: Zayed
authors.affiliation: Imaging Institute, Cleveland Clinic, Abu Dhabi, United Arab Emirates.
authors.forename: Mohammad Asif
authors.initials: MA
authors.lastname: Dogar
authors.affiliation: Department of Radiology, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Ibrahim A
authors.initials: IA
authors.lastname: Alorainy
authors.affiliation: Department of Radiology, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Abdullah Abu
authors.initials: AA
authors.lastname: Jamea
authors.affiliation: Department of Ophthalmology, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Khaled
authors.initials: K
authors.lastname: Abu-Amero
authors.affiliation: Department of Pediatrics and Neurology, Arkansas Children's Hospital and University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: May
authors.initials: M
authors.lastname: Griebel
authors.affiliation: Department of Pediatrics and Neurology, Arkansas Children's Hospital and University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Wendy
authors.initials: W
authors.lastname: Ward
authors.affiliation: Allen Institute for Brain Science, Seattle, Washington, USA.
authors.forename: Ed S
authors.identifier: http://orcid.org/0000-0001-9012-6552
authors.initials: ES
authors.lastname: Lein
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts, USA.|Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.|Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts, USA.|Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Kyriacos
authors.identifier: http://orcid.org/0000-0003-0214-6014
authors.initials: K
authors.lastname: Markianos
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California, USA.
authors.forename: A James
authors.initials: AJ
authors.lastname: Barkovich
authors.affiliation: Department of Radiology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Caroline D
authors.identifier: http://orcid.org/0000-0001-5592-249X
authors.initials: CD
authors.lastname: Robson
authors.affiliation: Fetal-Neonatal Neuroimaging and Developmental Science Center, Division of Newborn Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.|Department of Radiology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: P Ellen
authors.initials: PE
authors.lastname: Grant
authors.affiliation: The Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland, USA, and Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Bosley
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts, USA.|Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts, USA.|Howard Hughes Medical Institute, Boston Children's Hospital, Boston, Massachusetts, USA.|Fetal-Neonatal Neuroimaging and Developmental Science Center, Division of Newborn Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.|Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Department of Ophthalmology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Engle
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts, USA.|Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.|Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts, USA.|Howard Hughes Medical Institute, Boston Children's Hospital, Boston, Massachusetts, USA.|Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Christopher A
authors.identifier: http://orcid.org/0000-0002-0156-2238
authors.initials: CA
authors.lastname: Walsh
authors.affiliation: Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts, USA.|Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.|Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Timothy W
authors.identifier: http://orcid.org/0000-0003-2988-7701
authors.initials: TW
authors.lastname: Yu
mesh_terms: D001921:Brain / Q000002:abnormalities*; D002490:Central Nervous System / Q000002:abnormalities; D015179:Colorectal Neoplasms / Q000235:genetics*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics; D019656:Loss of Heterozygosity / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics*; D009474:Neurons / Q000378:metabolism; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics
chemical_list: D011956:Receptors, Cell Surface