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

Journal article

Publication Details

Author(s): Konrad E, Nardini N, Caliebe A, Nagel I, Young D, Horvath G, Santoro SL, Shuss C, Ziegler A, Bonneau D, Kempers M, Pfundt R, Legius E, Bouman A, Stuurman KE, Õunap K, Pajusalu S, Wojcik MH, Vasileiou G, Le Guyader G, Schnelle HM, Berland S, Zonneveld-Huijssoon E, Kersten S, Gupta A, Blackburn PR, Ellingson MS, Ferber MJ, Dhamija R, Klee EW, McEntagart M, Lichtenbelt KD, Kenney A, Vergano SA, Abou Jamra R, Platzer K, Ella Pierpont M, Khattar D, Hopkin RJ, Martin RJ, Jongmans MC, Chang VY, Martinez-Agosto JA, Kuismin O, Kurki MI, Pietiläinen O, Palotie A, Maarup TJ, Johnson DS, Venborg Pedersen K, Laulund LW, Lynch SA, Blyth M, Prescott K, Canham N, Ibitoye R, Brilstra EH, Shinawi M, Fassi E, Sticht H, Gregor A, Van Esch H, Zweier C
Journal: Genetics in Medicine
Publication year: 2019
ISSN: 1098-3600


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.

FAU Authors / FAU Editors

Gregor, Anne Dr. rer. nat.
Humangenetisches Institut
Konrad, Enrico
Humangenetisches Institut
Sticht, Heinrich Prof. Dr.
Professur für Bioinformatik

External institutions with authors

Broad Institute
Centre hospitalier universitaire (CHU) d'Angers
Centre hospitalier universitaire de Poitiers (CHU de Poitiers)
Chapel Allerton Hospital
Children's Hospital of The King's Daughters
Cincinnati Children's Hospital Medical Center
Erasmus University Medical Center (MC)
Haukeland University Hospital / Haukeland universitetssykehus
Helsingin yliopisto / University of Helsinki
Kaiser Permanente
London North West Healthcare NHS Trust
Mayo Clinic
Mayo Clinic Phoenix
Nationwide Children's Hospital
Newcastle upon Tyne Hospitals NHS Foundation Trust
Odense Universitetshospital (OUH)
Radboud University Nijmegen Medical Centre / Radboudumc of voluit Radboud Universitair Medisch Centrum (UMC)
Sheffield Children's NHS Foundation Trust
Tartu University Hospital
Universität Leipzig
Universitätsklinikum Schleswig-Holstein (UKSH)
University College Dublin (UCD)
University Hospital Leuven (UZ) / Universitaire ziekenhuizen Leuven
University Medical Centre Utrecht (UMC Utrecht)
University of California Los Angeles (UCLA)
University of Groningen / Rijksuniversiteit Groningen
University of London
University of Minnesota (UMN)
Vancouver General Hospital
Washington University

How to cite

Konrad, E., Nardini, N., Caliebe, A., Nagel, I., Young, D., Horvath, G.,... Zweier, C. (2019). CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum. Genetics in Medicine. https://dx.doi.org/10.1038/s41436-019-0585-z

Konrad, Enrico, et al. "CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum." Genetics in Medicine (2019).


Last updated on 2019-12-07 at 12:53