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

Lookup NU author(s): Dr Richard Martin

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This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0).


Abstract

© 2019, The Author(s).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.


Publication metadata

Author(s): Konrad EDH, 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, Ounap 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 MCJ, Chang VY, Martinez-Agosto JA, Kuismin O, Kurki MI, Pietilainen 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

Publication type: Article

Publication status: Published

Journal: Genetics in Medicine

Year: 2019

Volume: 21

Pages: 2723-2733

Print publication date: 01/12/2019

Online publication date: 26/06/2019

Acceptance date: 06/06/2019

Date deposited: 09/07/2019

ISSN (print): 1098-3600

ISSN (electronic): 1530-0366

Publisher: Nature Publishing Group

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

DOI: 10.1038/s41436-019-0585-z


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Funding

Funder referenceFunder name
270949263/GRK2162
HICF-1009-003
INST 410/91-1 FUGG
Interdisciplinary Center for Clinical Research in Erlangen
National Human Genome Research Institute
National Heart, Lung, and Blood Institute
PRG471
PUT355
WT098051
ZW184/1-2
PUTJD827
T32GM007748
Wellcome Trust
ZW184/3-1

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