|Title||CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum.|
|Publication Type||Journal Article|
|Year of Publication||2019|
|Authors||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, 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 Authors||DDD study|
|Date Published||2019 12|
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 ofCTCF-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 Journal||Genet. Med.|
|PubMed Central ID||PMC6892744|
|Grant List||WT098051 / WT / Wellcome Trust / United Kingdom |
HICF-1009-003 / DH / Department of Health / United Kingdom
UM1 HG008900 / HG / NHGRI NIH HHS / United States
T32GM007748 / NH / NIH HHS / United States