Human Gene Module / Chromosome 19 / CIC

CICcapicua transcriptional repressor

Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
2 / 4
Rare Variants / Common Variants
9 / 0
Aliases
CIC
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Functional
Chromosome Band
19q13.2
Associated Disorders
EPS, ASD
Relevance to Autism

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.

Reports related to CIC (4 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support A de novo paradigm for mental retardation. Vissers LE , et al. (2010) No -
2 Primary The contribution of de novo coding mutations to autism spectrum disorder. Iossifov I , et al. (2014) Yes -
3 Recent Recommendation Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. C Yuen RK , et al. (2017) Yes -
4 Recent Recommendation Disruption of the ATXN1-CIC complex causes a spectrum of neurobehavioral phenotypes in mice and humans. Lu HC , et al. (2017) No ASDor autistic features, epilepsy/seizures
Rare Variants   (9)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1474C>T p.Arg492Trp missense_variant De novo - Simplex 21076407 Vissers LE , et al. (2010)
c.820C>T p.Arg274Ter stop_gained De novo - Simplex 25363768 Iossifov I , et al. (2014)
c.457C>T p.Leu153Phe missense_variant De novo - Simplex 25363768 Iossifov I , et al. (2014)
c.1582C>T p.Arg528Ter stop_gained De novo - Simplex 28263302 C Yuen RK , et al. (2017)
c.673C>T p.Gln225Ter stop_gained Familial - Simplex 28263302 C Yuen RK , et al. (2017)
c.1057C>T p.Arg353Ter stop_gained De novo - Simplex 28288114 Lu HC , et al. (2017)
c.1801_1808dupAAGAGACC p.Glu604ArgfsTer127 frameshift_variant De novo - Multiplex (presumed germline mosaicism) 28288114 Lu HC , et al. (2017)
c.2571_2578delinsC p.Thr859AlafsTer63 frameshift_variant De novo - Simplex 28288114 Lu HC , et al. (2017)
c.2974C>T p.Gln992Ter stop_gained Familial Paternal Simplex 28288114 Lu HC , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, Syndromic

2S

Score Delta: Increased from 2S to 3.3 + acc + S

2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

4/1/2018
2S
icon
3.3 + acc + S

Increased from 2S to 3.3 + acc + S

Description

2S

4/1/2017
icon
2S

Increased from to 2S

Description

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.

Krishnan Probability Score

Score 0.52813854445231

Ranking 1582/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
ExAC Score

Score 0.99990294666404

Ranking 674/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Iossifov Probability Score

Score 0.937

Ranking 98/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Sanders TADA Score

Score 0.69031812599129

Ranking 1098/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Zhang D Score

Score 0.43008652689634

Ranking 1117/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
CNVs associated with CIC(1 CNVs)
19q13.2 17 Deletion-Duplication 28  /  492
Submit New Gene

Report an Error