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

Purpose: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individualswith a neurodevelopmental disorder (NDD). Methods: Through international collaboration we collected data from 39subjects with variants in CTCF. We performedtranscriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impactof Ctcf dosage alteration on nervous systemdevelopment and function. Results: The individuals in our cohort carried 2 deletions, 8 likelygene-disruptive, 2 splice-site, and 20 different missense variants, most of themde novo. Two cases were familial. The associated phenotype was of variableseverity extending from mild developmental delay or normal IQ to severeintellectual disability. Feeding difficulties and behavioral abnormalities werecommon, and variable other findings including growth restriction and cardiacdefects were observed. RNA-sequencing in five individuals identified 3828deregulated genes enriched for known NDD genes and biological processes such astranscriptional regulation. Ctcf dosagealteration in Drosophila resulted in impairedgross neurological functioning and learning and memory deficits. Conclusion: We significantly broaden the mutational and clinical spectrum ofCTCF-associated NDDs. Our data shed lightonto the functional role of CTCF by identifying deregulated genes and show thatCtcf alterations result in nervous system defects in Drosophila.