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

TitleCTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum.
Publication TypeJournal Article
Year of Publication2019
AuthorsKonrad, 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, 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, Jamra, RAbou, Platzer, K, Pierpont, MElla, Khattar, D, Hopkin, RJ, Martin, RJ, Jongmans, MCJ, Chang, VY, Martinez-Agosto, JA, Kuismin, O, Kurki, MI, Pietiläinen, O, Palotie, A, Maarup, TJ, Johnson, DS, Pedersen, KVenborg, 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
Corporate AuthorsDDD study
JournalGenet Med
Date Published2019 Jun 26

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.

Alternate JournalGenet. Med.
PubMed ID31239556
Grant ListZW184/1-2 / / Deutsche Forschungsgemeinschaft /
ZW184/3-1 / / Deutsche Forschungsgemeinschaft /
270949263/GRK2162 / / Deutsche Forschungsgemeinschaft /
E26 / / IZKF, Medizinische Fakultät, Friedrich-Alexander-Universität Erlangen-Nürnberg (DE) /
0000 / / FWO Vlaanderen /
WT098051 / / Wellcome Trust / United Kingdom
HICF-1009-003 / / Health Innovation Challenge Fund /
UM1 HG008900 / / National Human Genome Research Institute /
PUT355 / / Estonian Research Council /
PRG471 / / Estonian Research Council /
PUTJD827 / / Estonian Research Council /
T32GM007748 / / National Institutes of Health /
0000 / / ELAN-Fonds, FAU Erlangen-Nürnberg /