DE NOVO MUTATIONS IN THE GENOME ORGANIZER CTCF CAUSE INTELLECTUAL DISABILITY. C. Zweier1, A. Gregor1, M. Oti2, E. N. Kouwenhoven2, J. Hoyer1, H. Sticht3, A. B. Ekici1, S. Kjaergaard4, A. Rauch5, H. G. Stunnenberg6, S. Uebe1, G. Vasileiou1, A. Reis1, H. Zhou2,7 1) Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; 2) Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; 3) Bioinformatics, Institute of Biochemistry, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany; 4) Department of Clinical Genetics, University Hospital of Copenhagen, Rigshospitalet, Copenhagen, Denmark; 5) Institute of Medical Genetics, University of Zurich, Schwerzenbach, Switzerland; 6) Department of Molecular Biology, Faculty of Science, Radboud University Nijmegen, Nijmegen, The Netherlands; 7) Department of Molecular Developmental Biology, Faculty of Science, Radboud University Nijmegen, Nijmegen, The Netherlands.

   An increasing number of genes involved in chromatin structure and epigenetic regulation has been implicated in a variety of developmental disorders, often including intellectual disability. By trio exome sequencing and subsequent mutational screening we now identified two de novo frameshift mutations and one de novo missense mutation in the CTCF gene in individuals with intellectual disability, microcephaly and growth retardation. Furthermore, a patient with a larger deletion including CTCF was identified. CTCF (CCCTC-binding factor) is one of the most important chromatin organizers in vertebrates and is involved in various chromatin regulation processes such as higher order of chromatin organization, enhancer function, and maintenance of three-dimensional chromatin structure. This crucial role in gene regulation prompted us to perform whole transcriptome analyses in blood lymphocytes of three of the patients and eight healthy controls. We found a broad deregulation of genes with a significant overlap between the patients. Down-regulated genes were enriched for genes involved in signal transduction and cell-environment interaction, processes which have been implicated in developmental and cognitive disorders. Together with data from chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) of CTCF in lymphocytes and publicly available ChIA-Pet data of CTCF from the related K562 cell line, we found that CTCF is important for enhancer-driven gene activation and that haploinsufficiency of CTCF affects the genomic interaction of enhancers and their regulated gene promoters that drive developmental processes and cognition.

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