Homo sapiens Exome

Autism spectrum disorders encompass a wide spectrum of neurodevelopmental impairments associated with defects in social response and communication that often occur in a context of intellectual disability. Rett syndrome is one example in which epilepsy, motor impairment and motor disturbance may co-occur. The disturbance of the epigenetic brain landscape, including patterns of post- translational modifications of histones, is increasingly recognized as a critical factor in the origin of neurodevelopmental disorders. Mutations in histone demethylases are known to occur in several autistic and intellectual disability- associated syndromes. Here we report the mutational analysis of the candidate histone demethylase JMJD1C (jumonji domain containing 1C) in 215 cases of autism spectrum disorders, intellectual disability and Rett syndrome without a known genetic defect. We found seven germline mutations in JMJD1C (jumonji domain containing 1C). These single nucleotide changes were not present in any control sample (~ 6,000) and caused an aminoacid change involving a different functional group. The functional study of a JMJD1C mutant Rett syndrome patient demonstrated that the altered protein had an abnormal subcellular localization and was unable to demethylate the DNA-damage response protein MDC1. We also confirmed that the wild-type JMJD1C protein is widely expressed in various human and mouse brain regions and that its depletion compromises dendritic activity. Our findings suggest that mutations in JMJD1C contribute to the development of autism spectrum disorders, including well defined clinical entities such as Rett syndrome.