Biallelic mutations in human DCC cause developmental split-brain syndrome

Nat Genet. 2017 Apr;49(4):606-612. doi: 10.1038/ng.3804.

Saumya S Jamuar ¹ ² ³ ⁴ ⁵, Klaus Schmitz-Abe ¹ ² ⁴, Alissa M D'Gama ¹ ⁴ ⁵, Marie Drottar ⁶, Wai-Man Chan ⁵ ⁶ ⁷ ⁸, Maya Peeva ⁶ ⁷ ⁸, Sarah Servattalab ¹ ⁴ ⁵, Anh-Thu N Lam ¹ ⁴ ⁵, Mauricio R Delgado ⁹ ¹⁰, Nancy J Clegg ⁹, Zayed Al Zayed ¹¹, Mohammad Asif Dogar ¹², Ibrahim A Alorainy ¹³, Abdullah Abu Jamea ¹³, Khaled Abu-Amero ¹⁴, May Griebel ¹⁵, Wendy Ward ¹⁵, Ed S Lein ¹⁶, Kyriacos Markianos ¹ ² ⁴ ¹⁷, A James Barkovich ¹⁸, Caroline D Robson ¹⁹, P Ellen Grant ⁶ ¹⁹, Thomas M Bosley ²⁰, Elizabeth C Engle ¹ ⁴ ⁵ ⁶ ⁷ ⁸ ²¹, Christopher A Walsh ¹ ² ⁴ ⁵ ⁷ ²¹, Timothy W Yu ¹ ² ²¹

Affiliations

1 Division of Genetics and Genomics, Boston Children's Hospital, Boston, Massachusetts, USA.
2 Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.
3 Department of Paediatrics, KK Women's and Children's Hospital, Paediatric Academic Clinical Programme, Duke-NUS Medical School, Singapore.
4 Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts, USA.
5 Howard Hughes Medical Institute, Boston Children's Hospital, Boston, Massachusetts, USA.
6 Fetal-Neonatal Neuroimaging and Developmental Science Center, Division of Newborn Medicine, Boston Children's Hospital, Boston, Massachusetts, USA.
7 Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
8 Department of Ophthalmology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
9 Department of Neurology, Texas Scottish Rite Hospital for Children, Dallas, Texas, USA.
10 Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA.
11 Department of Orthopedic Surgery, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
12 Imaging Institute, Cleveland Clinic, Abu Dhabi, United Arab Emirates.
13 Department of Radiology, King Saud University, Riyadh, Saudi Arabia.
14 Department of Ophthalmology, King Saud University, Riyadh, Saudi Arabia.
15 Department of Pediatrics and Neurology, Arkansas Children's Hospital and University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
16 Allen Institute for Brain Science, Seattle, Washington, USA.
17 Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA.
18 Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California, USA.
19 Department of Radiology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
20 The Wilmer Eye Institute, Johns Hopkins University, Baltimore, Maryland, USA, and Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
21 Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, Massachusetts, USA.

PMID: 28250456 DOI: 10.1038/ng.3804

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.

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