CIC encodes capicua, a transcriptional repressor that plays a role in the development of the central nervous system. CIC was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2017 (Lu et al., PMID: 28288114). The clinical features of affected individuals are variable and include developmental delay, intellectual disability, autism or autistic features, seizures and brain MRI abnormalities.
Eight variants (4 frameshift, 2 nonsense, and 2 missense) that have been reported in eight probands in four publications (PMIDs: 21076407, 24307393, 28288114, 35165976) are included in this curation. Most variants are de novo. Two affected siblings likely inherited the variant from a parent with germline mosaicism, and in another proband the variant was inherited from an unaffected parent with low level mosaicism (PMID: 28288114). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. CIC is highly constrained for truncating variants but not for missense variants (gnomAD v2.1.1). The mechanism of pathogenicity is loss of function.
This gene-disease relationship is also supported by experimental evidence, including conditional mouse models (PMID: 28288114) and functional alterations in patient and non-patient cells (PMIDs: 32820034, 35165976). CIC binds to the promoter of folate transport genes, including FOLR1; loss-of-function variants in CIC downregulate FOLR1 expression, leading to cerebral folate deficiency (PMID: 32820034).
In summary, there is definitive evidence supporting the relationship between CIC and autosomal dominant complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on January 18, 2023 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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