Human Gene Module / Chromosome 7 / ICA1

ICA1islet cell autoantigen 1

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
9 / 10
Rare Variants / Common Variants
10 / 0
Aliases
ICA1, ICA69,  ICAp69
Associated Syndromes
-
Chromosome Band
7p21.3
Associated Disorders
ID
Relevance to Autism

A rare duplication in the ICA1 gene has been identified with ASD (Salyakina et al., 2011).

Molecular Function

This gene encodes a protein with an arfaptin homology domain that is found both in the cytosol and as membrane-bound form on the Golgi complex and immature secretory granules. This protein is believed to be an autoantigen in insulin-dependent diabetes mellitus and primary Sjogren's syndrome.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to ICA1 (10 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Microduplications in an autism multiplex family narrow the region of susceptibility for developmental disorders on 15q24 and implicate 7p21 Cukier HN , et al. (2011) Yes -
2 Primary Copy number variants in extended autism spectrum disorder families reveal candidates potentially involved in autism risk Salyakina D , et al. (2011) Yes ID
3 Support De novo gene disruptions in children on the autistic spectrum Iossifov I , et al. (2012) Yes -
4 Support Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder Girirajan S , et al. (2013) Yes -
5 Support Prospective diagnostic analysis of copy number variants using SNP microarrays in individuals with autism spectrum disorders Nava C , et al. (2013) Yes ID
6 Recent Recommendation An interactome perturbation framework prioritizes damaging missense mutations for developmental disorders Chen S , et al. (2018) No -
7 Recent Recommendation Comparative Analyses of Copy-Number Variation in Autism Spectrum Disorder and Schizophrenia Reveal Etiological Overlap and Biological Insights Kushima I , et al. (2018) Yes -
8 Support Both rare and common genetic variants contribute to autism in the Faroe Islands Leblond CS , et al. (2019) Yes -
9 Support - Woodbury-Smith M et al. (2022) Yes -
10 Support - Zhou X et al. (2022) Yes -
Rare Variants   (10)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_gain Unknown - - 30208311 Kushima I , et al. (2018)
- - copy_number_loss Unknown - - 30208311 Kushima I , et al. (2018)
- - copy_number_gain Familial Maternal Simplex 23632794 Nava C , et al. (2013)
- - copy_number_gain Familial Paternal Simplex 23375656 Girirajan S , et al. (2013)
- - copy_number_gain Familial Paternal Multiplex 23375656 Girirajan S , et al. (2013)
c.1042A>C p.Thr348Pro missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1328A>G p.Gln443Arg missense_variant De novo - Simplex 22542183 Iossifov I , et al. (2012)
c.1494T>C p.Asp498%3D synonymous_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
- - copy_number_gain Familial Maternal Extended multiplex 22016809 Salyakina D , et al. (2011)
c.151del p.Ala51ProfsTer10 frameshift_variant Familial Paternal Simplex 30675382 Leblond CS , et al. (2019)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Rare inherited duplications of the 7p21 locus that included the ICA1 gene have been identified in ASD probands in multiple studies (Salyakina et al., 2011; Cukier et al., 2011; Girirajan et al., 2013; Nava et al., 2014). A rare de novo missense variant in the ICA1 gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2012. CNV analysis of 1,108 ASD cases, 2,458 schizophrenia (SCZ) cases, and 2,095 controls from a Japanese population in Kushima et al., 2018 demonstrated that significant enrichment of exonic CNVs affecting the ICA1 gene was observed in a combined cohort of ASD and SCZ cases compared to controls [2 CNVs from ASD cases and 4 CNVs from SCZ cases (6 total) vs. 0 CNVs in controls (Odds ratio 9.19, P = 1.0E-05)].

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
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.

10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

Rare inherited duplications of the 7p21 locus that included the ICA1 gene have been identified in ASD probands in multiple studies (Salyakina et al., 2011; Cukier et al., 2011; Girirajan et al., 2013; Nava et al., 2014). A rare de novo missense variant in the ICA1 gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2012. CNV analysis of 1,108 ASD cases, 2,458 schizophrenia (SCZ) cases, and 2,095 controls from a Japanese population in Kushima et al., 2018 demonstrated that significant enrichment of exonic CNVs affecting the ICA1 gene was observed in a combined cohort of ASD and SCZ cases compared to controls [2 CNVs from ASD cases and 4 CNVs from SCZ cases (6 total) vs. 0 CNVs in controls (Odds ratio 9.19, P = 1.0E-05)].

Reports Added
[New Scoring Scheme]
1/1/2019
3
icon
3

Decreased from 3 to 3

Description

Rare inherited duplications of the 7p21 locus that included the ICA1 gene have been identified in ASD probands in multiple studies (Salyakina et al., 2011; Cukier et al., 2011; Girirajan et al., 2013; Nava et al., 2014). A rare de novo missense variant in the ICA1 gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2012. CNV analysis of 1,108 ASD cases, 2,458 schizophrenia (SCZ) cases, and 2,095 controls from a Japanese population in Kushima et al., 2018 demonstrated that significant enrichment of exonic CNVs affecting the ICA1 gene was observed in a combined cohort of ASD and SCZ cases compared to controls [2 CNVs from ASD cases and 4 CNVs from SCZ cases (6 total) vs. 0 CNVs in controls (Odds ratio 9.19, P = 1.0E-05)].

Reports Added
[Both rare and common genetic variants contribute to autism in the Faroe Islands.2019]
10/1/2018
4
icon
3

Decreased from 4 to 3

Description

Rare inherited duplications of the 7p21 locus that included the ICA1 gene have been identified in ASD probands in multiple studies (Salyakina et al., 2011; Cukier et al., 2011; Girirajan et al., 2013; Nava et al., 2014). A rare de novo missense variant in the ICA1 gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2012. CNV analysis of 1,108 ASD cases, 2,458 schizophrenia (SCZ) cases, and 2,095 controls from a Japanese population in Kushima et al., 2018 demonstrated that significant enrichment of exonic CNVs affecting the ICA1 gene was observed in a combined cohort of ASD and SCZ cases compared to controls [2 CNVs from ASD cases and 4 CNVs from SCZ cases (6 total) vs. 0 CNVs in controls (Odds ratio 9.19, P = 1.0E-05)].

Reports Added
[Microduplications in an autism multiplex family narrow the region of susceptibility for developmental disorders on 15q24 and implicate 7p21.2011] [Comparative Analyses of Copy-Number Variation in Autism Spectrum Disorder and Schizophrenia Reveal Etiological Overlap and Biological Insights.2018]
7/1/2018
4
icon
4

Decreased from 4 to 4

Description

Rare duplications of 7p21 that include the ICA1 gene have been identified with ASD (Salyakina et al., 2011; Cukier et al., 2011).

Reports Added
[An interactome perturbation framework prioritizes damaging missense mutations for developmental disorders.2018]
7/1/2014
No data
icon
4

Increased from No data to 4

Description

Rare duplications of 7p21 that include the ICA1 gene have been identified with ASD (Salyakina et al., 2011; Cukier et al., 2011).

4/1/2014
No data
icon
4

Increased from No data to 4

Description

Rare duplications of 7p21 that include the ICA1 gene have been identified with ASD (Salyakina et al., 2011; Cukier et al., 2011).

Krishnan Probability Score

Score 0.56678514992753

Ranking 1203/25841 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.
Original Source
ExAC Score

Score 0.0049503682925165

Ranking 10590/18225 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
Original Source
Sanders TADA Score

Score 0.74952751905136

Ranking 1550/18665 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).
Original Source
Larsen Cumulative Evidence Score

Score 4

Ranking 311/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
Zhang D Score

Score 0.34202555317624

Ranking 2116/20870 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.
Original Source
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
STK16 serine/threonine kinase 16 Human Protein Binding 8576 O75716
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