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

• Published in: Genetics in medicine Vol. 21; no. 12; pp. 2723 - 2733
• Main Authors: Konrad, Enrico D. H., Nardini, Niels, Caliebe, Almuth, Nagel, Inga, Young, Dana, Horvath, Gabriella, Santoro, Stephanie L., Shuss, Christine, Ziegler, Alban, Bonneau, Dominique, Kempers, Marlies, Pfundt, Rolph, Legius, Eric, Bouman, Arjan, Stuurman, Kyra E., Õunap, Katrin, Pajusalu, Sander, Wojcik, Monica H., Vasileiou, Georgia, Le Guyader, Gwenaël, Schnelle, Hege M., Berland, Siren, Zonneveld-Huijssoon, Evelien, Kersten, Simone, Gupta, Aditi, Blackburn, Patrick R., Ellingson, Marissa S., Ferber, Matthew J., Dhamija, Radhika, Klee, Eric W., McEntagart, Meriel, Lichtenbelt, Klaske D., Kenney, Amy, Vergano, Samantha A., Abou Jamra, Rami, Platzer, Konrad, Ella Pierpont, Mary, Khattar, Divya, Hopkin, Robert J., Martin, Richard J., Jongmans, Marjolijn C. J., Chang, Vivian Y., Martinez-Agosto, Julian A., Kuismin, Outi, Kurki, Mitja I., Pietiläinen, Olli, Palotie, Aarno, Maarup, Timothy J., Johnson, Diana S., Venborg Pedersen, Katja, Laulund, Lone W., Lynch, Sally A., Blyth, Moira, Prescott, Katrina, Canham, Natalie, Ibitoye, Rita, Brilstra, Eva H., Shinawi, Marwan, Fassi, Emily, Sticht, Heinrich, Gregor, Anne, Van Esch, Hilde, Zweier, Christiane
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.12.2019; Elsevier Limited
• Subjects: Animals; Biomedical and Life Sciences; Biomedicine; CCCTC-Binding Factor - genetics; CCCTC-Binding Factor - metabolism; Child; Chromatin - genetics; Chromatin - metabolism; Developmental Disabilities - genetics; Drosophila melanogaster - genetics; Drosophila melanogaster - metabolism; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Exome Sequencing - methods; Female; Gene Expression Profiling - methods; Gene Expression Regulation - genetics; Human Genetics; Humans; Insects; Intellectual Disability - genetics; Laboratory Medicine; Male; Mutation - genetics; Mutation, Missense - genetics; Neurodevelopmental disorders; Neurodevelopmental Disorders - genetics; Neurodevelopmental Disorders - metabolism; Transcription Factors - genetics; Young Adult; chromatin organization; CTCF; neurodevelopmental disorders; intellectual disability; Drosophila melanogaster
• ISSN: 1098-3600; 1530-0366; 1530-0366
• DOI: 10.1038/s41436-019-0585-z

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 .