CIC

Gene Facts

• HGNC Symbol: CIC (HGNC:14214)
• HGNC Name: capicua transcriptional repressor
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: No previous names found
• Alias symbols: KIAA0306
• %HI: 37.93
• pLI: 1
• LOEUF: 0.25
• Cytoband: 19q13.2
• Genomic Coordinates:

  GRCh37/hg19:	chr19:42772682-42799948
  GRCh38/hg38:	chr19:42268530-42295796

• MANE Select Transcript: NM_001386298.1 ENST00000681038.1
• Function: Transcriptional repressor which plays a role in development of the central nervous system (CNS). In concert with ATXN1 and ATXN1L, involved in brain development. {ECO:0000250|UniProtKB:Q924A2}. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-14285
• ClinGen Curation ID: CCID:006869
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Sufficient Evidence for Haploinsufficiency (3)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 11/08/2022

Haploinsufficiency (HI) Score Details

• HI Score: 3
• HI Evidence Strength: Sufficient Evidence for Haploinsufficiency

HI Disease

• Complex Neurodevelopmental Disorder

HI Evidence

• PUBMED: 28288114
  Lu et al (2017) examined the roles of ATXN1-CIC complex in the mouse brain and discovered a cell-type- and region-specific role for this complex in neurobehavioral functions. Cic+/− mice exhibited mild hyperactivity compared to their wildtype littermate controls. Their studies showed that the ATXN1-CIC complex plays critical roles in brain development that affect behavior, and that ATXN1 and ATXN1L execute their functions mainly through forming a complex with CIC. They identified heterozygous truncating or frameshift variants in CIC that are predicted to undergo nonsense-mediated decay in five patients from four unrelated families with autosomal dominant intellectual disability-45 (MRD45). All variants were de novo. Of note, two affected sibs likely inherited the variant from one of the unaffected gonadal mosaic parent. Another patient inherited the variant from his unaffected father who was low-level mosaic (~15%) for the variant. All patients showed a spectrum of phenotypes, including developmental delay/intellectual disability (DD/ID), attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and seizures. The CIC variants in all affected individuals were confirmed by Sanger sequencing. Besides the CIC variants, no clinically significant variants were identified in known disease-causing genes. Fibroblasts derived from one patient showed almost 50% decrease in both protein and RNA levels, consistent with haploinsufficiency.
• PUBMED: 28263302
  Yuen et al (2017) identified a de novo heterozygous nonsense variant in CIC in a patient with autism spectrum disorder by performing whole genome sequencing.
• PUBMED: 22542183
  Iossifov et al (2012) identified a de novo heterozygous nonsense variant in a patient with autism spectrum disorder
• PUBMED: 35165976
  Sharma et al (2022) describe 4 probands with sequence variants predicted to result in putative haploinsufficiency of CIC. Three of 4 were de novo frameshift or nonsense variants. The 4th proband had a missense variant, but only maternal follow-up done (paternal testing not available). All probands had combination of learning delays, DD/ID, seizures and/or autism.
• PUBMED: 34117072
  Singh et al (2021) discuss whole gene deletions of CIC involved in multi-gene microdeletions in combination with ERF (known to cause craniosynostosis type 4). of 3 total probands with deletions detected by array, 2 probands described had deletion of CIC and ERF. Both were de novo origin. While ERF is the likely factor involved in patient phenotypes of macrocephaly and dysmorphic features, both patients also had global delays, seizures, and intellectual disability. A 3rd proband had a smaller deletion of just ERF which was maternally inherited. Mom and child with mild delays but no seizures. The two deletions involving CIC involved additional OMIM genes, but only ERF and CIC are currently thought to have phenotypes secondary to haploinsufficiency.
• PUBMED: 30504930
  Guo et al (2019) detected a de novo frameshift sequence variant in a proband through a genome sequencing study for simplex and multiplex families with ASD. The proband was formally diagnosed with autism by the DSM-5 and evaluated through the SAGE collective, however additional clinical information was not provided since criteria for this study only required a clinical diagnosis of autism.

• HI Evidence Comments: The CIC (capicua transcriptional repressor) gene encodes a transcriptional repressor that interacts with ATXN1 (OMIM 601556). ATXN1-CIC complex has a cell-type- and region-specific role for in neurobehavioral functions in mice brain. Several de novo heterozygous loss-of-function variants have been identified in individuals with neurodevelopmental disorders, including autism spectrum disorder, developmental delay, intellectual disability, and seizures. As yet, intragenic or entire deletions of CIC have not been reported. Additional reference: Vissers et al. (2010) identified a de novo heterozygous missense variant in CIC in a patient with intellectual disability using whole exome sequencing (21076407).

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity
• TS Evidence Comments: At this time there is no evidence that supports the triplosensitivity of CIC.