CICcapicua transcriptional repressor
Autism Reports / Total Reports
11 / 16Rare Variants / Common Variants
28 / 0Chromosome Band
19q13.2Associated Disorders
ASD, EPSGenetic Category
Rare Single Gene Mutation, Syndromic, FunctionalRelevance 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.
External Links
SFARI Genomic Platforms
Reports related to CIC (16 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 |
5 | Support | Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes | Guo H , et al. (2018) | Yes | - |
6 | Support | Utility of clinical exome sequencing in a complex Emirati pediatric cohort | Mahfouz NA et al. (2020) | Yes | - |
7 | Support | - | Wilfert AB et al. (2021) | Yes | - |
8 | Support | - | Sharma S et al. (2022) | No | ASD, ID, epilepsy/seizures |
9 | Support | - | Zhou X et al. (2022) | Yes | - |
10 | Support | - | Chan AJS et al. (2022) | Yes | - |
11 | Support | - | Wang J et al. (2023) | Yes | - |
12 | Support | - | Sheth F et al. (2023) | Yes | DD, ID |
13 | Support | - | Karthika Ajit Valaparambil et al. () | No | - |
14 | Support | - | Omri Bar et al. (2024) | Yes | Learning disability |
15 | Support | - | Axel Schmidt et al. (2024) | No | - |
16 | Support | - | Suhua Chang et al. () | Yes | - |
Rare Variants (28)
Status | Allele Change | Residue Change | Variant Type | Inheritance Pattern | Parental Transmission | Family Type | PubMed ID | Author, Year |
---|---|---|---|---|---|---|---|---|
c.7187-8A>G | - | splice_region_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
c.673C>T | p.Arg225Cys | stop_gained | De novo | - | - | 35165976 | Sharma S et al. (2022) | |
c.1057C>T | p.Arg353Ter | stop_gained | De novo | - | Simplex | 28288114 | Lu HC , et al. (2017) | |
c.673C>T | p.Arg225Cys | stop_gained | Familial | - | Simplex | 28263302 | C Yuen RK et al. (2017) | |
c.1582C>T | p.Arg528Ter | stop_gained | De novo | - | Simplex | 28263302 | C Yuen RK et al. (2017) | |
c.820C>T | p.Arg274Ter | stop_gained | De novo | - | Simplex | 25363768 | Iossifov I et al. (2014) | |
c.4265C>T | p.Ser1422Leu | missense_variant | De novo | - | - | 39039281 | Axel Schmidt et al. (2024) | |
c.1852G>A | p.Ala618Thr | missense_variant | Unknown | - | Simplex | 37543562 | Sheth F et al. (2023) | |
c.3547C>T | p.Arg1183Ter | stop_gained | Familial | - | Simplex | 34312540 | Wilfert AB et al. (2021) | |
c.7480C>T | p.Gln2494Ter | stop_gained | Familial | - | Simplex | 34312540 | Wilfert AB et al. (2021) | |
c.1015G>C | p.Glu339Gln | missense_variant | De novo | - | Multiplex | 35982159 | Zhou X et al. (2022) | |
c.6746A>C | p.Lys2249Thr | missense_variant | De novo | - | Simplex | 39126614 | Suhua Chang et al. () | |
c.457C>T | p.Pro153Ser | missense_variant | De novo | - | Simplex | 25363768 | Iossifov I et al. (2014) | |
c.2864C>T | p.Pro955Leu | stop_gained | Familial | Paternal | Simplex | 28288114 | Lu HC , et al. (2017) | |
c.1100dup | p.Pro368AlafsTer16 | frameshift_variant | De novo | - | - | 35165976 | Sharma S et al. (2022) | |
c.1474C>T | p.Arg492Trp | missense_variant | De novo | - | Simplex | 21076407 | Vissers LE , et al. (2010) | |
c.683G>A | p.Arg228Gln | missense_variant | Unknown | Not maternal | - | 35165976 | Sharma S et al. (2022) | |
c.1927G>C | p.Gly643Arg | missense_variant | Unknown | - | Multiplex | 32382396 | Mahfouz NA et al. (2020) | |
c.65del | p.Pro22GlnfsTer8 | frameshift_variant | Familial | Paternal | - | 36309498 | Chan AJS et al. (2022) | |
c.1246dup | p.Leu416ProfsTer138 | frameshift_variant | De novo | - | Simplex | 37393044 | Wang J et al. (2023) | |
c.3439_3440del | p.Trp1147ValfsTer76 | frameshift_variant | De novo | - | - | 35165976 | Sharma S et al. (2022) | |
c.4427C>T | p.Thr1476Ile | missense_variant | Unknown | - | - | 37943464 | Karthika Ajit Valaparambil et al. () | |
c.2323C>T | p.Arg775Cys | missense_variant | Familial | Paternal | Simplex | 38256266 | Omri Bar et al. (2024) | |
c.774_783del | p.Pro259ValfsTer88 | frameshift_variant | De novo | - | Simplex | 30504930 | Guo H , et al. (2018) | |
c.4143del | p.Asp1382ThrfsTer26 | frameshift_variant | Familial | - | Simplex | 34312540 | Wilfert AB et al. (2021) | |
c.6796del | p.Glu2266SerfsTer58 | frameshift_variant | Familial | - | Simplex | 34312540 | Wilfert AB et al. (2021) | |
c.2571_2578delinsC | p.Thr859AlafsTer63 | frameshift_variant | De novo | - | Simplex | 28288114 | Lu HC , et al. (2017) | |
c.4528_4535dup | p.Glu1513ArgfsTer127 | frameshift_variant | De novo | - | Multiplex (presumed germline mosaicism) | 28288114 | Lu HC , et al. (2017) |
Common Variants
No common variants reported.
SFARI Gene score
High Confidence
Score Delta: Score remained at 1
criteria met
See SFARI Gene'scoring criteriaWe 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.
4/1/2020
Score remained at 1
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.
10/1/2019
Decreased from 2S to 1
New Scoring Scheme
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.
Reports Added
[New Scoring Scheme]10/1/2018
Decreased from 2S 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.
4/1/2017
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
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ExAC Score
Score 0.99990294666404
Ranking 674/18225 scored genes
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Iossifov Probability Score
Score 0.937
Ranking 98/239 scored genes
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Sanders TADA Score
Score 0.69031812599129
Ranking 1098/18665 scored genes
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Zhang D Score
Score 0.43008652689634
Ranking 1117/20870 scored genes
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