University of Oulu

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., … Zweier, C. (2019). CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum. Genetics in Medicine, 21(12), 2723–2733.

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)
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Language: English
Published: Springer Nature, 2019
Publish Date: 2020-03-26


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.

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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
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
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.
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