CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum
2019
Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individuals
with a neurodevelopmental disorder (NDD). 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. 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. 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.
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