Human Gene Module / Chromosome 21 / SIK1

SIK1Salt-inducible kinase 1

SFARI Gene Score
S
Syndromic Syndromic
Autism Reports / Total Reports
3 / 8
Rare Variants / Common Variants
10 / 0
Aliases
SIK1, MSK,  SIK,  SNF1LK
Associated Syndromes
-
Chromosome Band
21q22.3
Associated Disorders
DD/NDD, ID, ASD
Relevance to Autism

Variants in the SIK1 gene were identified in six unrelated individuals presenting with developmental epilepsies; three subjects presenting with infantile spasms subsequently developed intractable epilepsy and an autism plus developmental disorder with absent speech, impaired socialization, and repetitive behaviors (Hansen et al., 2015).

Molecular Function

This gene encodes a serine/threonine-protein kinase involved in various processes such as cell cycle regulation, gluconeogenesis and lipogenesis regulation, muscle growth and differentiation and tumor suppression. It plays several roles in the central nervous system including regulation of the circadian clock (Jagannath et al., 2013) and transcription of corticotropin-releasing hormone in the hypothalamus (Liu et al., 2012).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to SIK1 (8 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Salt-inducible kinase is involved in the regulation of corticotropin-releasing hormone transcription in hypothalamic neurons in rats Liu Y , et al. (2011) No -
2 Support The CRTC1-SIK1 pathway regulates entrainment of the circadian clock Jagannath A , et al. (2013) No -
3 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
4 Primary De novo mutations in SIK1 cause a spectrum of developmental epilepsies Hansen J , et al. (2015) No DD, ID, autistic features
5 Support Epilepsy-causing sequence variations in SIK1 disrupt synaptic activity response gene expression and affect neuronal morphology Prschel C , et al. (2016) No -
6 Support - Badawi M et al. (2021) Yes Developmental and epileptic encephalopathy-30
7 Support - Zhou X et al. (2022) Yes -
8 Support - Sanchis-Juan A et al. (2023) No -
Rare Variants   (10)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1039G>T p.Glu347Ter stop_gained Unknown - - 25839329 Hansen J , et al. (2015)
c.1840C>T p.Gln614Ter stop_gained De novo - - 25839329 Hansen J , et al. (2015)
c.1897C>T p.Gln633Ter stop_gained Unknown - - 25839329 Hansen J , et al. (2015)
c.1475C>T p.Ser492Phe missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.895C>A p.Pro287Thr missense_variant De novo - - 25839329 Hansen J , et al. (2015)
c.1231A>T p.Ser411Cys missense_variant De novo - - 25839329 Hansen J , et al. (2015)
c.1906G>A p.Gly636Ser missense_variant De novo - - 25839329 Hansen J , et al. (2015)
c.991T>A p.Tyr331Asn missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.301A>G p.Ile101Val missense_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.1676G>C p.Gly559Ala missense_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

Variants in the SIK1 gene were identified in six unrelated individuals presenting with developmental epilepsies; three subjects presenting with infantile spasms subsequently developed intractable epilepsy and an autism plus developmental disorder with absent speech, impaired socialization, and repetitive behaviors (Hansen et al., 2015). Prschel et al., 2017 subsequently determined that SIK1 variants reported in Hansen et al., 2015 disrupted synaptic activity response gene expression and affected neuronal morphology. A novel de novo missense variant that was predicted to be damaging was observed in the SIK1 gene in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. SIK1 has been shown to be involved in the regulation of corticotropin-releasing hormone transcription in hypothalamic neurons in rats (Liu et al., 2012) and in regulating entrainment of the circadian clock (Jagannath et al., 2013).

Score Delta: Score remained at S

criteria met
See SFARI Gene'scoring criteria
S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

10/1/2019
S
icon
S

Score remained at S

New Scoring Scheme
Description

Variants in the SIK1 gene were identified in six unrelated individuals presenting with developmental epilepsies; three subjects presenting with infantile spasms subsequently developed intractable epilepsy and an autism plus developmental disorder with absent speech, impaired socialization, and repetitive behaviors (Hansen et al., 2015). Prschel et al., 2017 subsequently determined that SIK1 variants reported in Hansen et al., 2015 disrupted synaptic activity response gene expression and affected neuronal morphology. A novel de novo missense variant that was predicted to be damaging was observed in the SIK1 gene in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014. SIK1 has been shown to be involved in the regulation of corticotropin-releasing hormone transcription in hypothalamic neurons in rats (Liu et al., 2012) and in regulating entrainment of the circadian clock (Jagannath et al., 2013).

Reports Added
[New Scoring Scheme]
Krishnan Probability Score

Score 0.44727680036886

Ranking 13156/25841 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 0.99383046504274

Ranking 1618/18225 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 0.78912339544942

Ranking 2032/18665 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 0.26067808779085

Ranking 3319/20870 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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