CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum
| Autor: | Enrico D.H. Konrad, Niels Nardini, Almuth Caliebe, Inga Nagel, Dana Young, Gabriella Horvath, Stephanie L. Santoro, Christine Shuss, Alban Ziegler, Dominique Bonneau, Marlies Kempers, Rolph Pfundt, Eric Legius, Arjan Bouman, Kyra E. Stuurman, Katrin Õunap, Sander Pajusalu, Monica H. Wojcik, Georgia Vasileiou, Gwenaël Le Guyader, Hege M. Schnelle, Siren Berland, Evelien Zonneveld-Huijssoon, Simone Kersten, Aditi Gupta, Patrick R. Blackburn, Marissa S. Ellingson, Matthew J. Ferber, Radhika Dhamija, Eric W. Klee, Meriel McEntagart, Klaske D. Lichtenbelt, Amy Kenney, Samantha A. Vergano, Rami Abou Jamra, Konrad Platzer, Mary Ella Pierpont, Divya Khattar, Robert J. Hopkin, Richard J. Martin, Marjolijn C.J. Jongmans, Vivian Y. Chang, Julian A. Martinez-Agosto, Outi Kuismin, Mitja I. Kurki, Olli Pietiläinen, Aarno Palotie, Timothy J. Maarup, Diana S. Johnson, Katja Venborg Pedersen, Lone W. Laulund, Sally A. Lynch, Moira Blyth, Katrina Prescott, Natalie Canham, Rita Ibitoye, Eva H. Brilstra, Marwan Shinawi, Emily Fassi, Heinrich Sticht, Anne Gregor, Hilde Van Esch, Christiane Zweier |
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| Přispěvatelé: | Graduate School, Clinical Genetics, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, University of Helsinki, Center for Population, Health and Society, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Male
CCCTC-Binding Factor Developmental Disabilities lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] Transcriptome 0302 clinical medicine Neurodevelopmental disorder Intellectual disability Drosophila Proteins Missense mutation TOOL Genetics(clinical) Child Genetics (clinical) Genetics & Heredity Genetics 0303 health sciences biology GENE ONTOLOGY neurodevelopmental disorders 1184 Genetics developmental biology physiology HUMANS Chromatin 3. Good health DROSOPHILA Drosophila melanogaster intellectual disability LIBRARY Female INACTIVATION Life Sciences & Biomedicine Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] EXPRESSION DATABASE Mutation Missense Article Young Adult 03 medical and health sciences Exome Sequencing medicine Animals Gene 030304 developmental biology Science & Technology Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] Gene Expression Profiling biology.organism_classification medicine.disease CTCF Gene Expression Regulation DE-NOVO MUTATIONS Mutation 030217 neurology & neurosurgery Transcription Factors chromatin organization |
| Zdroj: | Genetics in Medicine, 21, 2723. Lippincott Williams and Wilkins Genetics in medicine, 21(12), 2723-2733. Lippincott Williams and Wilkins Konrad, E D H, Nardini, N, Caliebe, A, Nagel, I, Young, D, Horvath, G, Santoro, S L, Shuss, C, Ziegler, A, Bonneau, D, Kempers, M, Pfundt, R, Legius, E, Bouman, A, Stuurman, K E, Õunap, K, Pajusalu, S, Wojcik, M H, Vasileiou, G, Le Guyader, G, Schnelle, H M, Berland, S, Zonneveld-Huijssoon, E, Kersten, S, Gupta, A, Blackburn, P R, Ellingson, M S, Ferber, M J, Dhamija, R, Klee, E W, McEntagart, M, Lichtenbelt, K D, Kenney, A, Vergano, S A, Abou Jamra, R, Platzer, K, Ella Pierpont, M, Khattar, D, Hopkin, R J, Martin, R J, Jongmans, M C J, Chang, V Y, Martinez-Agosto, J A, Kuismin, O, Kurki, M I, Pietiläinen, O, Palotie, A, Maarup, T J, Venborg Pedersen, K, Laulund, L W & DDD Study 2019, ' CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum ', Genetics in Medicine, vol. 21, no. 12, pp. 2723-2733 . https://doi.org/10.1038/s41436-019-0585-z Genetics in Medicine, 21(12), 2723-2733. Lippincott Williams & Wilkins Genetics in Medicine, 21, 2723-2733 Genetics in Medicine, 21(12), 2723-2733. Nature Publishing Group Genetics in Medicine, 21, 12, pp. 2723-2733 Genetics in Medicine |
| ISSN: | 1098-3600 |
| DOI: | 10.1038/s41436-019-0585-z |
| Popis: | PURPOSE: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individuals with a neurodevelopmental disorder (NDD). METHODS: Through international collaboration we collected data from 39 subjects with variants in CTCF. We performed transcriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impact of Ctcf dosage alteration on nervous system development and function. RESULTS: The individuals in our cohort carried 2 deletions, 8 likely gene-disruptive, 2 splice-site, and 20 different missense variants, most of them de novo. Two cases were familial. The associated phenotype was of variable severity extending from mild developmental delay or normal IQ to severe intellectual disability. Feeding difficulties and behavioral abnormalities were common, and variable other findings including growth restriction and cardiac defects were observed. RNA-sequencing in five individuals identified 3828 deregulated genes enriched for known NDD genes and biological processes such as transcriptional regulation. Ctcf dosage alteration in Drosophila resulted in impaired gross neurological functioning and learning and memory deficits. CONCLUSION: We significantly broaden the mutational and clinical spectrum ofCTCF-associated NDDs. Our data shed light onto the functional role of CTCF by identifying deregulated genes and show that Ctcf alterations result in nervous system defects in Drosophila. ispartof: GENETICS IN MEDICINE vol:21 issue:12 pages:2723-2733 ispartof: location:United States status: published |
| Databáze: | OpenAIRE |
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