Novel CIC variants identified in individuals with neurodevelopmental phenotypes

Area of Science:

• Genetics
• Molecular Biology
• Neuroscience

Background:

• Heterozygous pathogenic variants in the CIC gene are associated with neurodevelopmental phenotypes.
• Eleven CIC variants are currently linked to CIC-related neurodevelopmental syndrome.

Purpose of the Study:

• To describe novel CIC variants in individuals with neurodevelopmental delay.
• To investigate the functional consequences of CIC variants on gene regulation.

Main Methods:

• Genetic sequencing to identify CIC variants.
• Functional studies to assess the impact of variants on CIC transcriptional repressor activity.
• Analysis of CIC target gene expression.

Main Results:

• Three novel and one previously reported CIC variants were identified in four individuals with neurodevelopmental delay.
• A de novo frameshift variant in CIC-L was identified in an individual with speech delay, intellectual disability, and autism spectrum disorder.
• Functional studies indicated that partial loss of CIC-L function leads to transcriptional derepression of target genes, and a missense variant showed partial loss of repressor activity.

Conclusions:

• The study expands the known spectrum of pathogenic CIC variants.
• Evidence supports CIC haploinsufficiency or partial loss of function as a mechanism for neurodevelopmental phenotypes.
• Findings contribute to understanding the genetic basis of neurodevelopmental disorders.