PURPOSE: Autism spectrum disorders are associated with defects in social response and communication that often occur in the context of intellectual disability. Rett syndrome is one example in which epilepsy, motor impairment, and motor disturbance may co-occur. Mutations in histone demethylases are known to occur in several of these syndromes. Herein, we aimed to identify whether mutations in the candidate histone demethylase JMJD1C (jumonji domain containing 1C) are implicated in these disorders. METHODS: We performed the mutational and functional analysis of JMJD1C in 215 cases of autism spectrum disorders, intellectual disability, and Rett syndrome without a known genetic defect. RESULTS: We found seven JMJD1C variants that were not present in any control sample ( 6,000) and caused an amino acid change involving a different functional group. From these, two de novo JMJD1C germline mutations were identified in a case of Rett syndrome and in a patient with intellectual disability. The functional study of the JMJD1C mutant Rett syndrome patient demonstrated that the altered protein had abnormal subcellular localization, diminished activity to demethylate the DNA damage-response protein MDC1, and reduced binding to MECP2. We confirmed that JMJD1C protein is widely expressed in brain regions and that its depletion compromises dendritic activity. CONCLUSIONS: Our findings indicate that mutations in JMJD1C contribute to the development of Rett syndrome and intellectual disability.Genet Med 18 1, 378-385.

This study was supported by the European Community’s Seventh Framework Program (FP7/2007–2013) under grant agreement PITN-GA-2012–316758 of the EPITRAIN project and PITN-GA-2009–238242 of DISCHROM; ERC grant agreement 268626 of the EPINORC project; the E-RARE EuroRETT network (Carlos III Health Institute project PI071327); the Fondation Lejeune (France); MINECO projects SAF2011-22803 and CSD2006-00049; the Cellex Foundation; the Botín Foundation; the Catalan Association for Rett Syndrome; Fundación Alicia Koplowitz 2011 Grant AKOPLOWITZ11_006; the FIS project PI1002512; Grants PI10/01422, PI13/00285, CA10/01474, RD06/0020/1050, RD12/0036/008, and 2009-SGR293; and the Health and Science Departments of the Catalan government (Generalitat de Catalunya). K.S. and P.P. are EPITRAIN Research Fellows. M.E. is an ICREA Research Professor.