Human Gene Module / Chromosome 16 / CASKIN1

CASKIN1CASK interacting protein 1

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
6 / 9
Rare Variants / Common Variants
15 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
16p13.3
Associated Disorders
-
Relevance to Autism

CASKIN1 was identified as an ASD candidate gene based on having a p-value < 0.001 following DeNovoWEST analysis of de novo variants in 16,877 ASD trios from the Simons Simplex Collection, the Autism Sequencing Consortium, the MSSNG cohort, and the SPARK cohort in Zhou et al., 2022; among the de novo variants observed in ASD cases in this analysis were a de novo loss-of-function variant and three damaging de novo missense variants (defined as having a REVEL score > 0.5). Subsequent gene-based meta-analysis involving de novo variant enrichment, transmission disequilibrium testing (TDT) of rare, inherited LoFs from unaffected parents to affected offspring, and comparisons of loss-of-function variants in cases vs population controls in this report found that CASKIN1 exhibited a nominal enrichment of loss-of-function variants in cases vs. controls (p = 0.02). CASKIN1 was also identifeid as an ASD candidate gene based on having a false discovery rate (FDR) < 0.001 following joint analysis of protein-truncating variants, missense variants, and copy number variants in a cohort of 63,237 individuals in Fu et al., 2022. Wilfert et al., 2021 identified two ultra-rare inherited frameshift variants in CASKIN1 that were exclusively transmitted to ASD probands from two independent families. Caskin1-knockout mice were found to exhibit differences in gait, enhanced nociception, anxiety-like behavior, strong freezing responses in contextual and cued-fear conditioning tests, and low memory retention in the Barnes Maze test, suggesting that Caskin1 contributes to a wide spectrum of behavioral phenotypes (Katano et al., 2018).

Molecular Function

Enables identical protein binding activity. Predicted to be involved in signal transduction. Predicted to be active in cytoplasm and membrane. Immunoprecipitation studies in Tabuchi et al., 2002 demonstrated that Caskin1 stably binds to CASK in the brain, while affinity chromatography experiments determined that Caskin1 coassembles with CASK on the immobilized cytoplasmic tail of neurexin-1. Bencsik et al., 2019 found that, In cultured Caskin knockout hippocampal neurons, overexpressed Caskin1 was enriched in dendritic spine heads and increased the amount of mushroom-shaped dendritic spines; furthermore, the authors found that Shank2, a master scaffold of the postsynaptic density, and Caskin1 co-localized within the same complex.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
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Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to CASKIN1 (9 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support - Tabuchi K et al. (2002) No -
2 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
3 Support - Katano T et al. (2018) No -
4 Support - Bencsik N et al. (2019) No -
5 Support - Wilfert AB et al. (2021) Yes -
6 Primary - Zhou X et al. (2022) Yes -
7 Recent Recommendation - Fu JM et al. (2022) Yes -
8 Support - More RP et al. (2023) Yes -
9 Support - Asmaa Ali Alharbi et al. (2024) Yes ADHD, epilepsy/seizures
Rare Variants   (15)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.263A>C p.Tyr88Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.481G>A p.Val161Ile missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.758A>G p.Tyr253Cys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1193G>A p.Arg398Gln missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1333C>T p.Arg445Trp missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2351G>T p.Arg784Leu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.4247G>C p.Gly1416Ala missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.322G>A p.Val108Met missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1152T>G p.Gly384%3D synonymous_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.2778C>T p.Ala926%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.2117C>T p.Ser706Leu missense_variant Familial - Multiplex 36702863 More RP et al. (2023)
c.2217del p.Arg740GlyfsTer65 frameshift_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1250C>T p.Thr417Met missense_variant De novo - Simplex 38721139 Asmaa Ali Alharbi et al. (2024)
c.1421_1422del p.Ser474Ter frameshift_variant Familial - Simplex 34312540 Wilfert AB et al. (2021)
c.2968del p.Ala990ProfsTer12 frameshift_variant Familial - Simplex 34312540 Wilfert AB et al. (2021)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

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.

10/1/2022
icon
2

Increased from to 2

Krishnan Probability Score

Score 0.49081045403137

Ranking 5957/25841 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 0.99995629537399

Ranking 574/18225 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 0.94642278001289

Ranking 16864/18665 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
Zhang D Score

Score 0.054476638301142

Ranking 7117/20870 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
CNVs associated with CASKIN1(1 CNVs)
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16p13.3 69 Deletion-Duplication 99  /  539
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