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

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 (2019)

Publication Language: English

Publication Type: Journal article

Publication year: 2019


Book Volume: 21

Pages Range: 2723-2733

Journal Issue: 12

DOI: 10.1038/s41436-019-0585-z


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.

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Eli and Edythe L. Broad Institute of MIT and Harvard US United States (USA) (US) Radboud University Nijmegen Medical Centre / Radboudumc of voluit Radboud Universitair Medisch Centrum (UMC) NL Netherlands (NL) Chapel Allerton Hospital GB United Kingdom (GB) University College Dublin (UCD) IE Ireland (IE) Nationwide Children's Hospital US United States (USA) (US) Centre hospitalier universitaire (CHU) d'Angers FR France (FR) Haukeland University Hospital / Haukeland universitetssykehus NO Norway (NO) University Hospital Leuven (UZ) / Universitaire ziekenhuizen Leuven BE Belgium (BE) Universitätsklinikum Schleswig-Holstein (UKSH) DE Germany (DE) Cincinnati Children's Hospital Medical Center US United States (USA) (US) Mayo Clinic US United States (USA) (US) University Medical Centre Utrecht (UMC Utrecht) NL Netherlands (NL) Kaiser Permanente US United States (USA) (US) Odense Universitetshospital (OUH) DK Denmark (DK) Children's Hospital of The King's Daughters GB United Kingdom (GB) Universität Leipzig DE Germany (DE) Erasmus University Medical Center (MC) NL Netherlands (NL) Helsingin yliopisto / University of Helsinki FI Finland (FI) Washington University in St. Louis US United States (USA) (US) Sheffield Children's NHS Foundation Trust GB United Kingdom (GB) Tartu University Hospital EE Estonia (EE) University of California Los Angeles (UCLA) US United States (USA) (US) Mayo Clinic in Arizona US United States (USA) (US) Vancouver General Hospital CA Canada (CA) London North West Healthcare NHS Trust GB United Kingdom (GB) University of London GB United Kingdom (GB) University of Minnesota (UMN) US United States (USA) (US) University of Groningen / Rijksuniversiteit Groningen NL Netherlands (NL) Newcastle upon Tyne Hospitals NHS Foundation Trust GB United Kingdom (GB) Centre hospitalier universitaire de Poitiers (CHU de Poitiers) FR France (FR)

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, 21(12), 2723-2733. https://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 21.12 (2019): 2723-2733.

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