CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum.
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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, DDD Study, Sticht Heinrich, Gregor Anne, Van Esch Hilde, Zweier Christiane
Аннотация
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.