Human Gene Module / Chromosome X / CASK

CASKcalcium/calmodulin dependent serine protein kinase

Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
4 / 16
Rare Variants / Common Variants
28 / 0
Aliases
CASK, CAGH39,  CAMGUK,  CMG,  FGS4,  LIN2,  MICPCH,  MRXSNA,  TNRC8
Associated Syndromes
FG syndrome 4
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
Xp11.4
Associated Disorders
DD/NDD, 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).

Reports related to CASK (16 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 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 -
3 Support A missense mutation in CASK causes FG syndrome in an Italian family. Piluso G , et al. (2009) No -
4 Support CASK mutations are frequent in males and cause X-linked nystagmus and variable XLMR phenotypes. Hackett A , et al. (2009) No Nystagmus
5 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
6 Support Large-scale discovery of novel genetic causes of developmental disorders. Deciphering Developmental Disorders Study (2014) No ASD
7 Recent Recommendation Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Stessman HA , et al. (2017) No -
8 Support Calcium/calmodulin-dependent serine protein kinase (CASK), a protein implicated in mental retardation and autism-spectrum disorders, interacts with... Huang TN and Hsueh YP (2017) No -
9 Support Comprehensive investigation of CASK mutations and other genetic etiologies in 41 patients with intellectual disability and microcephaly with pontin... Hayashi S , et al. (2017) No -
10 Support A novel CASK mutation identified in siblings exhibiting developmental disorders with/without microcephaly. Seto T , et al. (2017) Yes Microcephaly
11 Support Exome Pool-Seq in neurodevelopmental disorders. Popp B , et al. (2017) No Microcephaly
12 Support Two microcephaly-associated novel missense mutations in CASK specifically disrupt the CASK-neurexin interaction. LaConte LEW , et al. (2018) No DD, microcephaly
13 Support Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population. Monies D , et al. (2019) No Microcephaly
14 Support The Clinical and Genetic Features of Co-occurring Epilepsy and Autism Spectrum Disorder in Chinese Children. Long S , et al. (2019) Yes -
15 Support Characterization of intellectual disability and autism comorbidity through gene panel sequencing. Aspromonte MC , et al. (2019) Yes -
16 Support Targeted Next-Generation Sequencing in Patients with Suggestive X-Linked Intellectual Disability. Ibarluzea N , et al. (2020) No -
Rare Variants   (28)
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 NA - 19165920 Najm J , et al. (2009)
c.1915C>T p.Arg639Ter stop_gained De novo NA - 19165920 Najm J , et al. (2009)
c.2119C>T p.Gln707Ter stop_gained De novo NA - 31209962 Aspromonte MC , et al. (2019)
c.1556T>C p.Met519Thr missense_variant Unknown - - 29426960 LaConte LEW , et al. (2018)
c.1976G>A p.Gly659Asp missense_variant De novo NA - 29426960 LaConte LEW , et al. (2018)
c.68del p.Phe23SerfsTer18 frameshift_variant De novo NA - 29158550 Popp B , et al. (2017)
c.83G>T p.Arg28Leu missense_variant Familial Maternal - 19200522 Piluso G , et al. (2009)
c.1922G>A p.Arg641Lys missense_variant Familial Maternal - 31139143 Long S , et al. (2019)
c.1159T>C p.Tyr387His missense_variant De novo NA - 31209962 Aspromonte MC , et al. (2019)
c.589G>A p.Gly197Arg missense_variant De novo NA 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.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.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.831+1G>A - splice_site_variant De novo NA - 25533962 Deciphering Developmental Disorders Study (2014)
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 NA Multiplex 31130284 Monies D , et al. (2019)
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 NA 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 NA Simplex 25533962 Deciphering Developmental Disorders Study (2014)
ENST00000378168:c.239C>T p.Pro80Leu missense_variant De novo NA Simplex 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

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).

Score Delta: Score remained at 4

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.

1/1/2020
4
icon
4

Score remained at 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).

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).

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).

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).

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.
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
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).
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.
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