Human Gene Module / Chromosome X / CASK

CASKcalcium/calmodulin dependent serine protein kinase

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
6 / 30
Rare Variants / Common Variants
45 / 0
Aliases
CASK, CAGH39,  CAMGUK,  CMG,  FGS4,  LIN2,  MICPCH,  MRXSNA,  TNRC8
Associated Syndromes
FG syndrome 4
Chromosome Band
Xp11.4
Associated Disorders
DD/NDD, ADHD, ID, EPS, ASD
Relevance to Autism

A likely damaging missense variant in the CASK gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. A de novo possibly damaging missense variant in CASK was identified in a female proband from the Deciphering Developmental Disorders (DDD) study presenting with autism, ADHD, developmental delay, and hypotonia (PMID 25533962). Mutations in this gene are associated with FG syndrome 4 (OMIM 300422) and mental retardation and microcephaly with pontine and cerebellar hypoplasia (OMIM 300749). CASK interacts with the high confidence ASD gene TBR1 (Hsueh et al., 2000).

Molecular Function

This gene encodes a calcium/calmodulin-dependent serine protein kinase. The encoded protein is a MAGUK (membrane-associated guanylate kinase) protein family member. These proteins are scaffold proteins and the encoded protein is located at synapses in the brain. Mutations in this gene are associated with FG syndrome 4 (OMIM 300422) and mental retardation and microcephaly with pontine and cerebellar hypoplasia (OMIM 300749).

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to CASK (30 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Nuclear translocation and transcription regulation by the membrane-associated guanylate kinase CASK/LIN-2 Hsueh YP , et al. (2000) No -
2 Support - Wang GS , et al. (2004) No -
3 Support Mutations of CASK cause an X-linked brain malformation phenotype with microcephaly and hypoplasia of the brainstem and cerebellum Najm J , et al. (2009) No -
4 Support A missense mutation in CASK causes FG syndrome in an Italian family Piluso G , et al. (2009) No -
5 Support CASK mutations are frequent in males and cause X-linked nystagmus and variable XLMR phenotypes Hackett A , et al. (2009) No Nystagmus
6 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
7 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No ASD
8 Recent Recommendation Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases Stessman HA , et al. (2017) No -
9 Support Calcium/calmodulin-dependent serine protein kinase (CASK), a protein implicated in mental retardation and autism-spectrum disorders, interacts with T-Brain-1 (TBR1) to control extinction of associative memory in male mice Huang TN and Hsueh YP (2017) No -
10 Support Comprehensive investigation of CASK mutations and other genetic etiologies in 41 patients with intellectual disability and microcephaly with pontine and cerebellar hypoplasia (MICPCH) Hayashi S , et al. (2017) No -
11 Support A novel CASK mutation identified in siblings exhibiting developmental disorders with/without microcephaly Seto T , et al. (2017) Yes Microcephaly
12 Support Exome Pool-Seq in neurodevelopmental disorders Popp B , et al. (2017) No Microcephaly
13 Support Two microcephaly-associated novel missense mutations in CASK specifically disrupt the CASK-neurexin interaction LaConte LEW , et al. (2018) No DD, microcephaly
14 Support Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population Monies D , et al. (2019) No Microcephaly
15 Support The Clinical and Genetic Features of Co-occurring Epilepsy and Autism Spectrum Disorder in Chinese Children Long S , et al. (2019) Yes -
16 Support Characterization of intellectual disability and autism comorbidity through gene panel sequencing Aspromonte MC , et al. (2019) Yes -
17 Support Targeted Next-Generation Sequencing in Patients with Suggestive X-Linked Intellectual Disability Ibarluzea N , et al. (2020) No -
18 Support Survival of a male patient harboring CASK Arg27Ter mutation to adolescence Mukherjee K et al. (2020) No DD, ID, epilepsy/seizures
19 Support Presynaptic dysfunction in CASK-related neurodevelopmental disorders Becker M et al. (2020) No ADHD, ID, epilepsy/seizures
20 Support - Trakadis Y et al. (2021) No -
21 Support - Pode-Shakked B et al. (2021) No -
22 Support - Zhou X et al. (2022) Yes -
23 Support - McSweeney D et al. (2022) No -
24 Support - Abe-Hatano C et al. (2023) No -
25 Recent Recommendation - Timberlake AT et al. (2023) No -
26 Support - Sanchis-Juan A et al. (2023) No ID
27 Support - Karthika Ajit Valaparambil et al. () No -
28 Support - Lucie Sedlackova et al. (2024) No -
29 Support - Tamam Khalaf et al. (2024) Yes -
30 Support - Alistair T Pagnamenta et al. (2024) No -
Rare Variants   (45)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - inversion Unknown - - 19165920 Najm J , et al. (2009)
- - copy_number_loss - - - 19165920 Najm J , et al. (2009)
- - copy_number_loss De novo - - 19165920 Najm J , et al. (2009)
- - inversion Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
- - copy_number_gain De novo - Simplex 32929080 Becker M et al. (2020)
c.79C>T p.Arg27Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
- - copy_number_loss Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
- - inversion De novo - Simplex 38776926 Alistair T Pagnamenta et al. (2024)
c.1915C>T p.Arg639Ter stop_gained De novo - - 19165920 Najm J , et al. (2009)
c.589G>A p.Gly197Arg missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.725G>A p.Trp242Ter stop_gained De novo - - 36660024 Abe-Hatano C et al. (2023)
c.2119C>T p.Gln707Ter stop_gained De novo - - 31209962 Aspromonte MC , et al. (2019)
c.1610G>A p.Arg537Gln missense_variant Unknown - - 34363551 Trakadis Y et al. (2021)
c.79C>T p.Arg27Ter stop_gained De novo - Simplex 32696595 Mukherjee K et al. (2020)
c.1556T>C p.Met519Thr missense_variant Unknown - - 29426960 LaConte LEW , et al. (2018)
c.1976G>A p.Gly659Asp missense_variant De novo - - 29426960 LaConte LEW , et al. (2018)
c.1394C>G p.Ser465Cys missense_variant Unknown - - 38438125 Tamam Khalaf et al. (2024)
c.68del p.Phe23SerfsTer18 frameshift_variant De novo - - 29158550 Popp B , et al. (2017)
c.1159T>C p.Tyr387His missense_variant De novo - - 31209962 Aspromonte MC , et al. (2019)
c.83G>T p.Arg28Leu missense_variant Familial Maternal - 19200522 Piluso G , et al. (2009)
c.793A>T p.Ile265Phe missense_variant De novo - - 38008000 Lucie Sedlackova et al. (2024)
c.1922G>A p.Arg641Lys missense_variant Familial Maternal - 31139143 Long S , et al. (2019)
c.589G>A p.Gly197Arg missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.915G>A p.Lys305= splice_site_variant Unknown Not maternal - 19165920 Najm J , et al. (2009)
c.1682_1694del p.Gly561AlafsTer53 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.1314+1G>T - splice_site_variant Familial Maternal Multiplex 32929080 Becker M et al. (2020)
c.427A>G p.Lys143Glu missense_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.1610G>A p.Arg537Gln missense_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.1223G>A p.Arg408Lys missense_variant Unknown - - 37943464 Karthika Ajit Valaparambil et al. ()
c.1424G>T p.Ser475Ile missense_variant Familial Maternal Multiplex 28944139 Seto T , et al. (2017)
c.2521-2A>T p.? splice_site_variant Familial Maternal Multiplex 20029458 Hackett A , et al. (2009)
c.831+1G>A - splice_site_variant De novo - - 25533962 Deciphering Developmental Disorders Study (2014)
c.490G>A p.Gly164Arg missense_variant Familial Maternal Unknown 31906484 Ibarluzea N , et al. (2020)
c.2183A>G p.Lys728Arg missense_variant Familial Maternal Multiplex 20029458 Hackett A , et al. (2009)
c.2755T>C p.Trp919Arg missense_variant Familial Maternal Multiplex 20029458 Hackett A , et al. (2009)
c.1556T>C p.Met519Thr missense_variant Unknown Not maternal Simplex 29426960 LaConte LEW , et al. (2018)
c.1214_1215del p.Ala405GlyfsTer16 frameshift_variant De novo - Multiplex 31130284 Monies D , et al. (2019)
c.1623_1626del p.Ile542ValfsTer52 frameshift_variant De novo - Simplex 34580403 Pode-Shakked B et al. (2021)
c.802T>C p.Tyr268His missense_variant Familial Maternal Multi-generational 20029458 Hackett A , et al. (2009)
c.1186C>T p.Pro396Ser missense_variant Familial Maternal Extended multiplex 20029458 Hackett A , et al. (2009)
c.2129A>G p.Asp710Gly missense_variant Familial Maternal Extended multiplex 20029458 Hackett A , et al. (2009)
c.763C>T p.Arg255Cys missense_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.1768C>T p.Pro590Ser stop_gained Familial Maternal Simplex 25533962 Deciphering Developmental Disorders Study (2014)
ENST00000378168:c.10C>T p.Arg4Ter stop_gained De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
ENST00000378168:c.239C>T p.Pro80Leu missense_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

Score Delta: Score remained at 1

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 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.

10/1/2020
1
icon
1

Score remained at 1

Description

A likely damaging missense variant in the CASK gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. A de novo possibly damaging missense variant in CASK was identified in a female proband from the Deciphering Developmental Disorders (DDD) study presenting with autism, ADHD, developmental delay, and hypotonia (PMID 25533962). Mutations in this gene are associated with FG syndrome 4 (OMIM 300422) and mental retardation and microcephaly with pontine and cerebellar hypoplasia (OMIM 300749). CASK interacts with the high confidence ASD gene TBR1 (Hsueh et al., 2000).

Reports Added
[Presynaptic dysfunction in CASK-related neurodevelopmental disorders2020]
7/1/2020
1
icon
1

Score remained at 1

Description

A likely damaging missense variant in the CASK gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. A de novo possibly damaging missense variant in CASK was identified in a female proband from the Deciphering Developmental Disorders (DDD) study presenting with autism, ADHD, developmental delay, and hypotonia (PMID 25533962). Mutations in this gene are associated with FG syndrome 4 (OMIM 300422) and mental retardation and microcephaly with pontine and cerebellar hypoplasia (OMIM 300749). CASK interacts with the high confidence ASD gene TBR1 (Hsueh et al., 2000).

Reports Added
[Survival of a male patient harboring CASK Arg27Ter mutation to adolescence2020]
1/1/2020
1
icon
1

Score remained at 1

Description

A likely damaging missense variant in the CASK gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. A de novo possibly damaging missense variant in CASK was identified in a female proband from the Deciphering Developmental Disorders (DDD) study presenting with autism, ADHD, developmental delay, and hypotonia (PMID 25533962). Mutations in this gene are associated with FG syndrome 4 (OMIM 300422) and mental retardation and microcephaly with pontine and cerebellar hypoplasia (OMIM 300749). CASK interacts with the high confidence ASD gene TBR1 (Hsueh et al., 2000).

Reports Added
[Targeted Next-Generation Sequencing in Patients with Suggestive X-Linked Intellectual Disability.2020]
10/1/2019
4
icon
1

Decreased from 4 to 1

New Scoring Scheme
Description

A likely damaging missense variant in the CASK gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. A de novo possibly damaging missense variant in CASK was identified in a female proband from the Deciphering Developmental Disorders (DDD) study presenting with autism, ADHD, developmental delay, and hypotonia (PMID 25533962). Mutations in this gene are associated with FG syndrome 4 (OMIM 300422) and mental retardation and microcephaly with pontine and cerebellar hypoplasia (OMIM 300749). CASK interacts with the high confidence ASD gene TBR1 (Hsueh et al., 2000).

Reports Added
[New Scoring Scheme]
7/1/2019
4
icon
4

Decreased from 4 to 4

Description

A likely damaging missense variant in the CASK gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. A de novo possibly damaging missense variant in CASK was identified in a female proband from the Deciphering Developmental Disorders (DDD) study presenting with autism, ADHD, developmental delay, and hypotonia (PMID 25533962). Mutations in this gene are associated with FG syndrome 4 (OMIM 300422) and mental retardation and microcephaly with pontine and cerebellar hypoplasia (OMIM 300749). CASK interacts with the high confidence ASD gene TBR1 (Hsueh et al., 2000).

Reports Added
[Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population.2019] [The Clinical and Genetic Features of Co-occurring Epilepsy and Autism Spectrum Disorder in Chinese Children.2019] [Characterization of intellectual disability and autism comorbidity through gene panel sequencing.2019]
10/1/2017
4
icon
4

Decreased from 4 to 4

Description

A likely damaging missense variant in the CASK gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. A de novo possibly damaging missense variant in CASK was identified in a female proband from the Deciphering Developmental Disorders (DDD) study presenting with autism, ADHD, developmental delay, and hypotonia (PMID 25533962). Mutations in this gene are associated with FG syndrome 4 (OMIM 300422) and mental retardation and microcephaly with pontine and cerebellar hypoplasia (OMIM 300749). CASK interacts with the high confidence ASD gene TBR1 (Hsueh et al., 2000).

Reports Added
[A novel CASK mutation identified in siblings exhibiting developmental disorders with/without microcephaly.2017] [Exome Pool-Seq in neurodevelopmental disorders.2017]
7/1/2017
4
icon
4

Decreased from 4 to 4

Description

A likely damaging missense variant in the CASK gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. A de novo possibly damaging missense variant in CASK was identified in a female proband from the Deciphering Developmental Disorders (DDD) study presenting with autism, ADHD, developmental delay, and hypotonia (PMID 25533962). Mutations in this gene are associated with FG syndrome 4 (OMIM 300422) and mental retardation and microcephaly with pontine and cerebellar hypoplasia (OMIM 300749). CASK interacts with the high confidence ASD gene TBR1 (Hsueh et al., 2000).

Reports Added
[Comprehensive investigation of CASK mutations and other genetic etiologies in 41 patients with intellectual disability and microcephaly with pontin...2017]
1/1/2017
icon
4

Increased from to 4

Description

A likely damaging missense variant in the CASK gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. A de novo possibly damaging missense variant in CASK was identified in a female proband from the Deciphering Developmental Disorders (DDD) study presenting with autism, ADHD, developmental delay, and hypotonia (PMID 25533962). Mutations in this gene are associated with FG syndrome 4 (OMIM 300422) and mental retardation and microcephaly with pontine and cerebellar hypoplasia (OMIM 300749). CASK interacts with the high confidence ASD gene TBR1 (Hsueh et al., 2000).

Krishnan Probability Score

Score 0.5575638036057

Ranking 1334/25841 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 0.99988570450481

Ranking 697/18225 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 0.8294775216161

Ranking 2837/18665 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 0.32216950020118

Ranking 2405/20870 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
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