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

Genet Med. 2019 Dec;21(12):2723-2733. doi: 10.1038/s41436-019-0585-z. Epub 2019 Jun 26.

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 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.

Keywords: CTCF; Drosophila melanogaster; chromatin organization; intellectual disability; neurodevelopmental disorders.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CCCTC-Binding Factor / genetics*
  • CCCTC-Binding Factor / metabolism*
  • Child
  • Chromatin / genetics
  • Chromatin / metabolism
  • Developmental Disabilities / genetics
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / metabolism
  • Female
  • Gene Expression Profiling / methods
  • Gene Expression Regulation / genetics
  • Humans
  • Intellectual Disability / genetics
  • Male
  • Mutation / genetics
  • Mutation, Missense / genetics
  • Neurodevelopmental Disorders / genetics*
  • Neurodevelopmental Disorders / metabolism
  • Transcription Factors / genetics
  • Whole Exome Sequencing / methods
  • Young Adult

Substances

  • CCCTC-Binding Factor
  • CTCF protein, Drosophila
  • CTCF protein, human
  • Chromatin
  • Drosophila Proteins
  • Transcription Factors