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Genet Med. 2019 Jun 26. doi: 10.1038/s41436-019-0585-z. [Epub ahead of print]

CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum.

Author information

1
Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
2
Institute of Human Genetics, Universitätsklinikum Schleswig Holstein Campus Kiel and Christian-Albrechts-Universität, Kiel, Germany.
3
Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
4
Adult Metabolic Diseases Clinic, Vancouver General Hospital, Vancouver, BC, Canada.
5
Division of Molecular and Human Genetics, Nationwide Children's Hospital, Columbus, OH, USA.
6
Département de Biochimie et Génétique, CHU Angers et Mitolab INSERM 1083-CNRS 6015, Angers, France.
7
Department of Human Genetics, Radboud University Medical Center and Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
8
Department of Human Genetics, KU Leuven and Center for Human Genetics, University Hospital Leuven, KU Leuven, Leuven, Belgium.
9
Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.
10
Department of Clinical Genetics, United Laboratories, Tartu University Hospital, Tartu, Estonia.
11
Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
12
The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
13
Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
14
Divisions of Genetics and Genomics and Newborn Medicine, Department of Pediatrics, Boston Children's Hospital, Boston, MA, USA.
15
Service de Génétique Clinique, CHU de Poitiers, Poitiers, France.
16
Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.
17
Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
18
Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
19
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
20
Department of Clinical Genomics, Mayo Clinic, Scottsdale, AZ, USA.
21
South West Thames Regional Genetics Centre, St. George's Healthcare NHS Trust, St. George's, University of London, London, UK.
22
Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
23
Division of Medical Genetics and Metabolism, Children's Hospital of The King's Daughters, Norfolk, VA, USA.
24
Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
25
Department of Pediatrics, Division of Genetics and Metabolism, University of Minnesota, Minneapolis, MN, USA.
26
Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
27
The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
28
Division of Pediatric Hematology-Oncology, Department of Pediatrics, David Geffen School of Medicine, Los Angeles, CA, USA.
29
Jonsson Comprehensive Cancer Center, University of California, Los Angeles, CA, USA.
30
Division of Medical Genetics, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
31
Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
32
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
33
PEDEGO Research Unit, University of Oulu, Oulu, Finland.
34
Medical Research Center, Oulu University Hospital, University of Oulu, Oulu, Finland.
35
Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland.
36
Psychiatric & Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
37
The Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
38
Department of Stem Cell and Regenerative Biology, University of Harvard, Cambridge, MA, USA.
39
Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
40
Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
41
Department of Genetics, Kaiser Permanente, Los Angeles, CA, USA.
42
Sheffield Children's Hospital, Sheffield, UK.
43
Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
44
Department of Pediatrics, Odense University Hospital, Odense, Denmark.
45
University College Dublin and Temple Street Children's Hospital, Dublin, Ireland.
46
Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds Teaching Hospitals NHS Trust, Leeds, UK.
47
North West Thames Regional Genetics Service, Northwick Park Hospital, Harrow, UK.
48
Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA.
49
Institute of Biochemistry, Emil-Fischer Center, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
50
Center for Human Genetics, University Hospital Leuven, KU Leuven, Leuven, Belgium.
51
Institute of Human Genetics, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany. christiane.zweier@uk-erlangen.de.

Abstract

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 of CTCF-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.

KEYWORDS:

CTCF; Drosophila melanogaster; chromatin organization; intellectual disability; neurodevelopmental disorders

PMID:
31239556
DOI:
10.1038/s41436-019-0585-z

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