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 Type: Journal article

Publication year: 2019

Journal

DOI: 10.1038/s41436-019-0585-z

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.

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Involved external institutions

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

How to cite

APA:

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://doi.org/10.1038/s41436-019-0585-z

MLA:

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

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