Human Gene Module / Chromosome 5 / CAMK4

CAMK4calcium/calmodulin dependent protein kinase IV

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
6 / 6
Rare Variants / Common Variants
5 / 1
Aliases
CAMK4, CaMK IV,  CaMK-GR,  CaMKIV,  caMK
Associated Syndromes
-
Chromosome Band
5q22.1
Associated Disorders
EPS
Relevance to Autism

De novo variants in the CAMK4 gene have been identified in three individuals presenting with dystonia and involuntary movements including chorea or myoclonus, developmental delay, intellectual disability, and ASD and other behavioral problems (Zech et al., 2018; Zech et al., 2020; Zech et al., 2021). A coding-synonymous variant in the CAMK4 gene (rs25925) had previously been shown to associate with ASD [odds ratio 1.30 (95% CI 1.02-1.66), P value 0.035] in a family-based association study of 446 German families; the minor allele of this variant was predicted to alter exonic splicing enhancer elements, and quantitative PCR analysis demonstrated that homozygous carriers of the minor risk allele showed increased levels of a truncated CAMK4 isoform in blood (Waltes et al., 2014).

Molecular Function

The product of this gene belongs to the serine/threonine protein kinase family, and to the Ca(2+)/calmodulin-dependent protein kinase subfamily. This enzyme is a multifunctional serine/threonine protein kinase with limited tissue distribution, that has been implicated in transcriptional regulation in lymphocytes, neurons and male germ cells.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
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SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to CAMK4 (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Common variants in genes of the postsynaptic FMRP signalling pathway are risk factors for autism spectrum disorders Waltes R , et al. (2014) Yes -
2 Support - Zech M et al. (2018) Yes -
3 Support - Zech M et al. (2020) Yes -
4 Support - Zech M et al. (2021) Yes OCD, epilepsy/seizures
5 Support - Zhou X et al. (2022) Yes -
6 Support - Cirnigliaro M et al. (2023) Yes -
Rare Variants   (5)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.940C>T p.Gln314Ter stop_gained De novo - - 33211350 Zech M et al. (2021)
c.981+1G>A - splice_site_variant De novo - Simplex 30262571 Zech M et al. (2018)
c.981+1G>T - splice_site_variant De novo - Simplex 33098801 Zech M et al. (2020)
c.858G>A p.Lys286%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.303+2dup - splice_site_variant Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
Common Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.1011C=;c.1011C>G;c.420G>C p.(=) synonymous_variant, splice_site_variant - - - 24442360 Waltes R , et al. (2014)
SFARI Gene score
2

Strong Candidate

A coding-synonymous substitution variant in exon 11 of the CAMK4 gene (rs25925) associated with ASD in a discovery cohort of 446 German ASD families, as well as in a combined meta-analysis using a subsample of the Autism Genome Project and a French case/control cohort in addition to the original German discovery cohort (Waltes et al., 2014).

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.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

A coding-synonymous substitution variant in exon 11 of the CAMK4 gene (rs25925) associated with ASD in a discovery cohort of 446 German ASD families, as well as in a combined meta-analysis using a subsample of the Autism Genome Project and a French case/control cohort in addition to the original German discovery cohort (Waltes et al., 2014).

1/1/2021
3
icon
3

Decreased from 3 to 3

Description

A coding-synonymous substitution variant in exon 11 of the CAMK4 gene (rs25925) associated with ASD in a discovery cohort of 446 German ASD families, as well as in a combined meta-analysis using a subsample of the Autism Genome Project and a French case/control cohort in addition to the original German discovery cohort (Waltes et al., 2014).

Reports Added
[A unique de novo gain-of-function variant in CAMK4 associated with intellectual disability and hyperkinetic movement disorder2018] [Monogenic variants in dystonia: an exome-wide sequencing study2020] [A Neurodevelopmental Disorder With Dystonia and Chorea Resulting From Clustering CAMK4 Variants2021]
10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

A coding-synonymous substitution variant in exon 11 of the CAMK4 gene (rs25925) associated with ASD in a discovery cohort of 446 German ASD families, as well as in a combined meta-analysis using a subsample of the Autism Genome Project and a French case/control cohort in addition to the original German discovery cohort (Waltes et al., 2014).

Reports Added
[New Scoring Scheme]
7/1/2015
icon
4

Increased from to 4

Description

A coding-synonymous substitution variant in exon 11 of the CAMK4 gene (rs25925) associated with ASD in a discovery cohort of 446 German ASD families, as well as in a combined meta-analysis using a subsample of the Autism Genome Project and a French case/control cohort in addition to the original German discovery cohort (Waltes et al., 2014).

Krishnan Probability Score

Score 0.57444676991603

Ranking 673/25841 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 0.015829669761245

Ranking 9629/18225 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 0.86900965326935

Ranking 4254/18665 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 5

Ranking 276/461 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 0.70661484598876

Ranking 1/20870 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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