ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000019.9) (NC_000019.10)
Evidence for haploinsufficiency phenotype
PubMed ID Description
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.
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.
22542183 Iossifov et al (2012) identified a de novo heterozygous nonsense variant in a patient with autism spectrum disorder

Haploinsufficiency phenotype 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 seizure. As yet, intragenic or entire deletions of CIC have not been reported. Additional reference: Vissers at al (2010) identified a de novo heterozygous missense variant in CIC in a patient with intellectual disability using whole exome sequencing (21076407)

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

At this time there is no evidence that supports the triplosensitivity of CIC.