CIC haploinsufficiency syndrome (CHS) is caused by heterozygous loss of function mutations in the gene CIC.
The majority of mutations in CIC are loss of function truncating variants that are predicted to undergo nonsense mediated decay. Additionally, point mutations in DNA binding domains (HMG Box or C1 domain) have been observed and are predicted to be loss of function. Other missense variants in patients with neurobehavioral phenotypes have yet to be functionally validated but this is being actively investigated.
CIC encodes an HMG box transcription factor that represses target gene expression. Mouse models have demonstrated a critical role for CIC in development of multiple brain regions (cortex, hippocampus, hypothalamus, amygdala), intestines, and lungs.