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

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http://hdl.handle.net/10138/310447

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DDD Study , Konrad , E D H , Nardini , N , Kuismin , O , Kurki , M I , Pietiläinen , O & Palotie , A 2019 , ' CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum ' , Genetics In medicine , vol. 21 , no. 12 , pp. 2723-2733 . https://doi.org/10.1038/s41436-019-0585-z

Title: CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum
Author: DDD Study; Konrad, Enrico D. H.; Nardini, Niels; Kuismin, Outi; Kurki, Mitja I.; Pietiläinen, Olli; Palotie, Aarno
Contributor: University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Center for Population, Health and Society
University of Helsinki, Centre of Excellence in Complex Disease Genetics
Date: 2019-12
Language: eng
Number of pages: 11
Belongs to series: Genetics In medicine
ISSN: 1098-3600
URI: http://hdl.handle.net/10138/310447
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 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.
Subject: CTCF
neurodevelopmental disorders
Drosophila melanogaster
intellectual disability
chromatin organization
DE-NOVO MUTATIONS
GENE ONTOLOGY
EXPRESSION
DROSOPHILA
HUMANS
INACTIVATION
DATABASE
LIBRARY
TOOL
1184 Genetics, developmental biology, physiology
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