Human Gene Module / Chromosome 11 / BRSK2

BRSK2BR serine/threonine kinase 2

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
12 / 12
Rare Variants / Common Variants
33 / 0
EAGLE Score
7.7
Moderate Learn More
Aliases
BRSK2, C11orf7,  PEN11B,  SAD1,  SADA,  STK29
Associated Syndromes
-
Chromosome Band
11p15.5
Associated Disorders
-
Genetic Category
Rare Single Gene Mutation, Syndromic, Functional
Relevance to Autism

A de novo loss-of-function variant in the BRSK2 gene was identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014), while a de novo in-frame deletion variant in this gene was observed in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). Hiatt et al., 2019 identified nine individuals with rare heterozygous variants in the BRSK2 gene that presented with a neurodevelopmental disorder characterized by speech delay, intellectual disability, motor delay, autism, and behavioral abnormalities. Two additional de novo loss-of-function variants in this gene were identified in ASD probands from the SPARK cohort (Feliciano et al., 2019); in the same report, a meta-analysis of de novo variants in 4773 published ASD trios and 465 SPARK trios using TADA identified BRSK2 as an ASD candidate gene with a q-value 0.1. A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified BRSK2 as a gene reaching exome-wide significance (P < 2.5E-06). Hiatt et al., 2019 identified nine individuals with rare heterozygous variants in the BRSK2 gene that presented with a neurodevelopmental disorder characterized by speech delay, intellectual disability, motor delay, autism, and behavioral abnormalities.

Molecular Function

Serine/threonine-protein kinase that plays a key role in polarization of neurons and axonogenesis, cell cycle progress and insulin secretion.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to BRSK2 (12 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Recent Recommendation Deleterious Variation in BRSK2 Associates with a Neurodevelopmental Disorder Hiatt SM , et al. (2019) Yes Speech delay, motor delay, developmental regressio
4 Recent Recommendation Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
5 Support - Mahjani B et al. (2021) Yes -
6 Support - Woodbury-Smith M et al. (2022) Yes -
7 Support - Deng J et al. (2022) Yes DD
8 Support - Zhou X et al. (2022) Yes -
9 Support - Costa CIS et al. (2023) Yes -
10 Support - Wang J et al. (2023) Yes -
11 Support - Hu Y et al. (2023) Yes -
12 Support - et al. () Yes -
Rare Variants   (33)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- p.? splice_site_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.169G>T p.Glu57Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.272+2T>C - splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
c.977+5G>A - splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
c.664C>T p.Arg222Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.730C>T p.Gln244Ter stop_gained De novo - - 30879638 Hiatt SM , et al. (2019)
c.196G>A p.Glu66Lys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.951-1G>A - splice_site_variant De novo - - 31452935 Feliciano P et al. (2019)
c.772C>T p.Arg258Cys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1033C>T p.Pro345Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1190C>G p.Ala397Gly missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.168C>T p.Leu56%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.633G>C p.Leu211%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.664C>T p.Arg222Ter stop_gained De novo - Simplex 35754711 Deng J et al. (2022)
c.1861C>T p.Arg621Cys missense_variant Unknown - - 30879638 Hiatt SM , et al. (2019)
c.488C>T p.Ala163Val missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.273-1G>A p.? splice_site_variant De novo - Simplex 30879638 Hiatt SM , et al. (2019)
c.530+1G>A p.? splice_site_variant De novo - Simplex 30879638 Hiatt SM , et al. (2019)
c.194G>A p.Gly65Asp missense_variant De novo - Simplex 30879638 Hiatt SM , et al. (2019)
c.1321del p.Val441CysfsTer36 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.1737dup p.Ile580AspfsTer16 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.635G>A p.Gly212Glu missense_variant De novo - Simplex 30879638 Hiatt SM , et al. (2019)
c.1617A>C p.Lys539Asn missense_variant De novo - Simplex 37280359 Costa CIS et al. (2023)
c.1532dup p.Ser512ValfsTer84 frameshift_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.1491G>A p.Thr497%3D synonymous_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.442del p.Leu148CysfsTer39 frameshift_variant De novo - Simplex 37671287 Hu Y et al. (2023)
c.1501del p.Thr501ArgfsTer8 frameshift_variant De novo - - 31452935 Feliciano P et al. (2019)
c.992_994del p.Lys331del inframe_deletion De novo - Simplex 25363768 Iossifov I et al. (2014)
c.1301_1307del p.Val434AlafsTer41 frameshift_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1674_1675del p.Ser559ProfsTer36 frameshift_variant De novo - Simplex 37393044 Wang J et al. (2023)
c.1395_1396del p.Leu466PhefsTer129 frameshift_variant De novo - Simplex 30879638 Hiatt SM , et al. (2019)
c.1143_1154del p.Ser382_Val385del splice_site_variant Unknown - Unknown 30879638 Hiatt SM , et al. (2019)
c.1532_1533del p.Pro511LeufsTer84 frameshift_variant Unknown Not maternal - 30879638 Hiatt SM , et al. (2019)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

A de novo likely gene-disruptive variant in the BRSK2 gene was identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014), while a de novo in-frame deletion variant in this gene was observed in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). Hiatt et al., 2019 identified nine individuals with rare heterozygous variants in the BRSK2 gene that presented with a neurodevelopmental disorder characterized by speech delay, intellectual disability, motor delay, autism, and behavioral abnormalities. Two additional likely gene-disruptive variants in the BRSK2 gene were identified in ASD probands from the SPARK cohort in Feliciano et al., 2019; a meta-analysis of de novo variants in 4773 published ASD trios and 465 SPARK trios using TADA in the same report identified BRSK2 as an ASD candidate gene with a q-value 0.1.

Score Delta: Score remained at 1S

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.

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."

4/1/2022
S
icon
1

Increased from S to 1

Description

A de novo likely gene-disruptive variant in the BRSK2 gene was identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014), while a de novo in-frame deletion variant in this gene was observed in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). Hiatt et al., 2019 identified nine individuals with rare heterozygous variants in the BRSK2 gene that presented with a neurodevelopmental disorder characterized by speech delay, intellectual disability, motor delay, autism, and behavioral abnormalities. Two additional likely gene-disruptive variants in the BRSK2 gene were identified in ASD probands from the SPARK cohort in Feliciano et al., 2019; a meta-analysis of de novo variants in 4773 published ASD trios and 465 SPARK trios using TADA in the same report identified BRSK2 as an ASD candidate gene with a q-value 0.1.

10/1/2019
4S
icon
S

Decreased from 4S to S

New Scoring Scheme
Description

A de novo likely gene-disruptive variant in the BRSK2 gene was identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014), while a de novo in-frame deletion variant in this gene was observed in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). Hiatt et al., 2019 identified nine individuals with rare heterozygous variants in the BRSK2 gene that presented with a neurodevelopmental disorder characterized by speech delay, intellectual disability, motor delay, autism, and behavioral abnormalities. Two additional likely gene-disruptive variants in the BRSK2 gene were identified in ASD probands from the SPARK cohort in Feliciano et al., 2019; a meta-analysis of de novo variants in 4773 published ASD trios and 465 SPARK trios using TADA in the same report identified BRSK2 as an ASD candidate gene with a q-value 0.1.

Reports Added
[Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes2019] [New Scoring Scheme]
7/1/2019
icon
4S

Increased from to 4S

Description

A de novo loss-of-function variant in the BRSK2 gene was identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014), while a de novo in-frame deletion variant in this gene was observed in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). Hiatt et al., 2019 identified nine individuals with rare heterozygous variants in the BRSK2 gene that presented with a neurodevelopmental disorder characterized by speech delay, intellectual disability, motor delay, autism, and behavioral abnormalities.

Krishnan Probability Score

Score 0.53845003078592

Ranking 1458/25841 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 0.77957008109351

Ranking 4053/18225 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
Iossifov Probability Score

Score 0.929

Ranking 112/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Original Source
Sanders TADA Score

Score 0.31547514598275

Ranking 192/18665 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 0.44875490790258

Ranking 936/20870 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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