Biallelic mutations in human DCC cause developmental split-brain syndrome

Saumya S. Jamuar, Klaus Schmitz-Abe, Alissa M. D'Gama, Marie Drottar, Wai Man Chan, Maya Peeva, Sarah Servattalab, Anh Thu N. Lam, Mauricio R. Delgado, Nancy J. Clegg, Zayed Al Zayed, Mohammad Asif Dogar, Ibrahim A. Alorainy, Abdullah Abu Jamea, Khaled Abu-Amero, May Griebel, Wendy Ward, Ed S. Lein, Kyriacos Markianos, A. James BarkovichCaroline D. Robson, P. Ellen Grant, Thomas M. Bosley, Elizabeth C. Engle, Christopher A. Walsh, Timothy W. Yu

Research output: Contribution to journalArticlepeer-review

51 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)606-612
Number of pages7
JournalNature genetics
Issue number4
StatePublished - Mar 30 2017

ASJC Scopus subject areas

  • Genetics


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