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CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum |
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| Author: | Konrad, Enrico D. H.1; Nardini, Niels1; Caliebe, Almuth2; |
| Organizations: |
1Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany 2Institute of Human Genetics, Universitätsklinikum Schleswig Holstein Campus Kiel and Christian-Albrechts-Universität, Kiel, Germany 3Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
4Adult Metabolic Diseases Clinic, Vancouver General Hospital, Vancouver, BC, Canada
5Division of Molecular and Human Genetics, Nationwide Children’s Hospital, Columbus, OH, USA 6Département de Biochimie et Génétique, CHU Angers et Mitolab INSERM 1083—CNRS 6015, Angers, France 7Department of Human Genetics, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands 8Department of Human Genetics, KU Leuven and Center for Human Genetics, University Hospital Leuven, KU Leuven, Leuven, Belgium 9Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands 10Department of Clinical Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia 11Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia 12The Broad Institute of MIT and Harvard, Cambridge, MA, USA 13Department of Genetics, Yale University School of Medicine, New Haven, CT, USA 14Divisions of Genetics and Genomics and Newborn Medicine, Department of Pediatrics, Boston Children’s Hospital, Boston, MA, USA 15Service de Génétique Clinique, CHU de Poitiers, Poitiers, France 16Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway 17Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands 18Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA 19Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA 20Department of Clinical Genomics, Mayo Clinic, Scottsdale, AZ, USA 21South West Thames Regional Genetics Centre, St. George’s Healthcare NHS Trust, St. George’s, University of London, London, UK 22Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands 23Division of Medical Genetics and Metabolism, Children’s Hospital of The King’s Daughters, Norfolk, VA, USA 24Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany 25Department of Pediatrics, Division of Genetics and Metabolism, University of Minnesota, Minneapolis, MN, USA 26Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA 27The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK 28Division of Pediatric Hematology-Oncology, Department of Pediatrics, David Geffen School of Medicine, Los Angeles, CA, USA 29Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA 30Division of Medical Genetics, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA 31Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA 32Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland 33PEDEGO Research Unit, University of Oulu, Oulu, Finland 34Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland 35Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland 36Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA 37The Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA 38Department of Stem Cell and Regenerative Biology, University of Harvard, Cambridge, MA, USA 39Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA 40Department of Neurology, Massachusetts General Hospital, Boston, MA, USA 41Department of Genetics, Kaiser Permanente, Los Angeles, CA, USA 42Sheffield Children’s Hospital, Sheffield, UK 43Department of Clinical Genetics, Odense University Hospital, Odense, Denmark 44Department of Pediatrics, Odense University Hospital, Odense, Denmark 45University College Dublin and Temple Street Children’s Hospital, Dublin, Ireland 46Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, UK 47North West Thames Regional Genetics Service, Northwick Park Hospital, Harrow, UK 48Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA 49Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK 50Institute of Biochemistry, Emil- Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany 51Center for Human Genetics, University Hospital Leuven, KU Leuven, Leuven, Belgium |
| Format: | article |
| Version: | published version |
| Access: | open |
| Online Access: | PDF Full Text (PDF, 2 MB) |
| Persistent link: | http://urn.fi/urn:nbn:fi-fe202003269330 |
| Language: | English |
| Published: |
Springer Nature,
2019
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| Publish Date: | 2020-03-26 |
| Description: |
AbstractPurpose: 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. see all
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| Series: |
Genetics in medicine |
| ISSN: | 1098-3600 |
| ISSN-E: | 1530-0366 |
| ISSN-L: | 1098-3600 |
| Volume: | 21 |
| Issue: | 12 |
| Pages: | 2723 - 2733 |
| DOI: | 10.1038/s41436-019-0585-z |
| OADOI: | https://oadoi.org/10.1038/s41436-019-0585-z |
| Type of Publication: |
A1 Journal article – refereed |
| Field of Science: |
3111 Biomedicine |
| Subjects: | |
| Funding: |
We thank all individuals and families for participating in this study. We especially thank Laila Distel and Christine Suchy for excellent technical assistance; André Reis, Arif Ekici, and Fulvia Ferrazzi at the next-generation sequencing core facility at the Institute of Human Genetics in Erlangen; and Felix Engel for help with the confocal microscope, which was supported by the German Research Foundation (INST 410/91-1 FUGG). C.Z. is supported by grants from the German Research Foundation (ZW184/1-2, ZW184/3-1, and 270949263/GRK2162) and by the Interdisciplinary Center for Clinical Research in Erlangen (E26 and ELAN-Fonds). H.V.E. is a clinical investigator of FWO Vlaanderen. K.Õ. and S.P. received support from Estonian Research Council grants PUT355, PRG471, and PUTJD827. M.H.W. is supported by T32GM007748. This study makes use of data generated by the DECIPHER community. Funding for the project was provided by the Wellcome Trust. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute (grant number WT098051). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network. The Broad Center for Mendelian Genomics (UM1 HG008900) is funded by the National Human Genome Research Institute with supplemental funding provided by the National Heart, Lung, and Blood Institute under the Trans-Omics for Precision Medicine (TOPMed) program and the National Eye Institute. Please also see Supplementary Acknowledgements. |
| Copyright information: |
© The Authors 2019. This article is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. If you remix, transform, or build upon this article or a part thereof, you must distribute your contributions under the same license as the original. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/. |
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https://creativecommons.org/licenses/by-nc-sa/4.0/ |