@article {670, title = {CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum.}, journal = {Genet Med}, volume = {21}, year = {2019}, month = {2019 12}, pages = {2723-2733}, 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 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.

}, issn = {1530-0366}, doi = {10.1038/s41436-019-0585-z}, author = {Konrad, Enrico D H and Nardini, Niels and Caliebe, Almuth and Nagel, Inga and Young, Dana and Horvath, Gabriella and Santoro, Stephanie L and Shuss, Christine and Ziegler, Alban and Bonneau, Dominique and Kempers, Marlies and Pfundt, Rolph and Legius, Eric and Bouman, Arjan and Stuurman, Kyra E and {\~O}unap, Katrin and Pajusalu, Sander and Wojcik, Monica H and Vasileiou, Georgia and Le Guyader, Gwena{\"e}l and Schnelle, Hege M and Berland, Siren and Zonneveld-Huijssoon, Evelien and Kersten, Simone and Gupta, Aditi and Blackburn, Patrick R and Ellingson, Marissa S and Ferber, Matthew J and Dhamija, Radhika and Klee, Eric W and McEntagart, Meriel and Lichtenbelt, Klaske D and Kenney, Amy and Vergano, Samantha A and Abou Jamra, Rami and Platzer, Konrad and Ella Pierpont, Mary and Khattar, Divya and Hopkin, Robert J and Martin, Richard J and Jongmans, Marjolijn C J and Chang, Vivian Y and Martinez-Agosto, Julian A and Kuismin, Outi and Kurki, Mitja I and Pietil{\"a}inen, Olli and Palotie, Aarno and Maarup, Timothy J and Johnson, Diana S and Venborg Pedersen, Katja and Laulund, Lone W and Lynch, Sally A and Blyth, Moira and Prescott, Katrina and Canham, Natalie and Ibitoye, Rita and Brilstra, Eva H and Shinawi, Marwan and Fassi, Emily and Sticht, Heinrich and Gregor, Anne and Van Esch, Hilde and Zweier, Christiane} }