Novel CIC variants identified in individuals with neurodevelopmental phenotypes

Hum Mutat. 2022 Jul;43(7):889-899. doi: 10.1002/humu.24346. Epub 2022 Mar 2.


Heterozygous pathogenic variants in CIC, which encodes a transcriptional repressor, have been identified in individuals with neurodevelopmental phenotypes. To date, 11 CIC variants have been associated with the CIC-related neurodevelopmental syndrome. Here, we describe three novel and one previously reported CIC variants in four individuals with neurodevelopmental delay. Notably, we report for the first time a de novo frameshift variant specific to the long isoform of CIC (CIC-L, NM_001304815.1:c.1100dup, p.Pro368AlafsTer16) in an individual with speech delay, intellectual disability, and autism spectrum disorder. Our investigation into the function of CIC-L reveals that partial loss of CIC-L leads to transcriptional derepression of CIC target genes. We also describe a missense variant (NM_015125.3:c.683G>A, p.Arg228Gln) in an individual with a history of speech delay and relapsed pre-B acute lymphoblastic leukemia. Functional studies of this variant suggest a partial loss of CIC transcriptional repressor activity. Our study expands the list of CIC pathogenic variants and contributes to the accumulating evidence that CIC haploinsufficiency or partial loss of function is a pathogenic mechanism causing neurodevelopmental phenotypes.

Keywords: CIC haploinsufficiency; capicua; developmental delay; neurodevelopmental phenotypes; pre-B acute lymphoblastic leukemia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autism Spectrum Disorder* / genetics
  • Heterozygote
  • Humans
  • Intellectual Disability* / genetics
  • Intellectual Disability* / pathology
  • Language Development Disorders* / genetics
  • Neurodevelopmental Disorders* / genetics
  • Neurodevelopmental Disorders* / pathology
  • Phenotype