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

DDD Study

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19 Scopus citations


Purpose: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individualswith a neurodevelopmental disorder (NDD). Methods: Through international collaboration we collected data from 39subjects with variants in CTCF. We performedtranscriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impactof Ctcf dosage alteration on nervous systemdevelopment and function. Results: The individuals in our cohort carried 2 deletions, 8 likelygene-disruptive, 2 splice-site, and 20 different missense variants, most of themde novo. Two cases were familial. The associated phenotype was of variableseverity extending from mild developmental delay or normal IQ to severeintellectual disability. Feeding difficulties and behavioral abnormalities werecommon, and variable other findings including growth restriction and cardiacdefects were observed. RNA-sequencing in five individuals identified 3828deregulated genes enriched for known NDD genes and biological processes such astranscriptional regulation. Ctcf dosagealteration in Drosophila resulted in impairedgross neurological functioning and learning and memory deficits. Conclusion: We significantly broaden the mutational and clinical spectrum ofCTCF-associated NDDs. Our data shed lightonto the functional role of CTCF by identifying deregulated genes and show thatCtcf alterations result in nervous system defects in Drosophila.

Original languageEnglish (US)
Pages (from-to)2723-2733
Number of pages11
JournalGenetics in Medicine
Issue number12
StatePublished - Dec 1 2019

Bibliographical note

Funding Information:
We thank all individuals and families for participating in this study. We especially thank Laila Distel and Christine Suchy for excellent technical assistance; André Reis, Arif Ekici, and Fulvia Ferrazzi at the next-generation sequencing core facility at the Institute of Human Genetics in Erlangen; and Felix Engel for help with the confocal microscope, which was supported by the German Research Foundation (INST 410/91-1 FUGG). C.Z. is supported by grants from the German Research Foundation (ZW184/1-2, ZW184/3-1, and 270949263/GRK2162) and by the Interdisciplinary Center for Clinical Research in Erlangen (E26 and ELAN-Fonds). H.V.E. is a clinical investigator of FWO Vlaanderen. K.Õ. and S.P. received support from Estonian Research Council grants PUT355, PRG471, and PUTJD827. M.H.W. is supported by T32GM007748. This study makes use of data generated by the DECIPHER community. Funding for the project was provided by the Wellcome Trust. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between Wellcome and the Department of Health, and the Wellcome Sanger Institute (grant number WT098051). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network. The Broad Center for Mendelian Genomics (UM1 HG008900) is funded by the National Human Genome Research Institute with supplemental funding provided by the National Heart, Lung, and Blood Institute under the Trans-Omics for Precision Medicine (TOPMed) program and the National Eye Institute. Please also see Supplementary Acknowledgements.

Publisher Copyright:
© 2019, The Author(s).


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


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