A de novo loss-of-function (LoF) variant in the CIC gene was first identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). A second de novo LoF variant in this gene was identified by whole genome sequencing in an ASD proband from a simplex family as part of the MSSNG initiative in Yuen et al., 2017. Based on the discovery of two de novo LoF variants in ASD cases, a probability of LoF intolerance rate (pLI) > 0.9, and a higher-than expected mutation rate (a false discovery rate < 15%), CIC was determined to be an ASD candidate gene in Yuen et al., 2017. Lu et al., 2017 demonstrated that deletion of Cic from the developing mouse forebrain resulted in hyperactivity, impaired learning and memory, and abnormal maturation and maintainence of upper-layer cortical neurons, whereas deletion of Cic from the hypothalamus and medial amygdala resulted in abnormal social behavior in mice. Lu et al., 2017 also identified loss-of-function variants in CIC in five patients with similar clinical features, including developmental delay/intellectual disability, ASD/autistic features, and seizures.
Molecular Function
The protein encoded by this gene is an ortholog of the Drosophila melanogaster capicua gene, and is a member of the high mobility group (HMG)-box superfamily of transcriptional repressors. It may play a role in development of the central nervous system.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
The contribution of de novo coding mutations to autism spectrum disorder
Unveiling Hidden Genetic Architectures: Molecular Diagnostic Yield of Whole Exome Sequencing in 50 Children With Autism Spectrum Disorder Negative for Copy Number Variations
Next-generation phenotyping integrated in a national framework for patients with ultrarare disorders improves genetic diagnostics and yields new molecular findings
Rescue Type:
RESCUE-Pharmaceutical
Rescue Paradigm:
Emx1 driven Cic conditional knockouts (heterozygotes) were treated with low dose amphetamine (2 mg per kg body weight) immediately before experimentation to rescue hyperactivity phenotype
Treatment does not improve measured phenotype (was expected to do so)
Ameliorated
Treatment provides partial correction or improvement of measured phenotype
No adverse effect
Treatment does not affect the parameter adversely
Sustained effect
Treatment has long term effect of restoration or amelioration, tested AFTER stopping administration (not applied for continuing long-term treatment) . Will be applied only where treatment has had restorative effects during administration or in the first battery of tests conducted.
No sustained effect
Treatment has no long term of restoration or amelioration detectable, after stopping administration. Will be applied only where treatment has had restorative effects during administration or in the first battery of tests conducted.
Description: Mutants show decreased thickness of layers 2 and 3 but normal thinkness of layers 5 and 6 of the cerebral cortex, compared to controls. Exp Paradigm: Nissl staining was performed on brain sections.
Description: Mutants show decreased neuronal numbers in layers 2 and 3 but normal neuronal numbers in layers 5 and 6 of the cerebral cortex, compared to controls. in mutants, layers 2 and 3 specific neuronal markers (satb2 and cux1) were reduced but a layers 5 and 6 specific marker (ctip2) were not changed, compared to controls (5 weeks). mutants showed no change in cux1 and satb2 positive cells in layers 2 and 3 of the cortex at p0, comapared to controls but the cux1 and satb2 neuronal numbers declined at p5 and p10. Exp Paradigm: Nissl staining was performed on brain sections.
Description: Mutants show a decrease in satb2 and cux1 double positive cells, compared to controls, indicating a disruption in lamina specific cell types. Exp Paradigm: NA
Description: Mutants show decreased thickness of the dentate gyrus of the hippocampus but no change in the thickness of the ca1 and ca3 regions, compared to controls. Exp Paradigm: Nissl staining was performed on brain sections.
Dendritic architecture: dendritic tree complexity1
Decreased
Description: Mutants show decreased dendritic branching of pyramidal neurons in layers 2 and 3 of the cerebral cortex but show no change in branching of pyramidal neurons in layers 5 and 6 of the cerebral cortex, compared to controls. Exp Paradigm: Neurons were labeled with injection of low-titre aav-yfp at p0.
Description: Mutants show decreased expression of cic across all cortical layers and in whole brain lysates, compared to controls. Exp Paradigm: Immunohistochemistry
Description: Mutants show decreased expression of cic across all cortical layers and in whole brain lysates, compared to controls. Exp Paradigm: Western blot
