Human Gene Module / Chromosome X / RPS6KA3

RPS6KA3Ribosomal protein S6 kinase, 90kDa, polypeptide 3

SFARI Gene Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
7 / 20
Rare Variants / Common Variants
19 / 0
Aliases
RPS6KA3, RP11-393H10.3,  CLS,  HU-3,  ISPK-1,  MAPKAPK1B,  MRX19,  RSK,  RSK2,  S6K-alpha3,  p90-RSK2,  pp90RSK2
Associated Syndromes
Coffin-Lowry syndrome, Coffin-Lowry syndrome, DD, ID
Chromosome Band
Xp22.12
Associated Disorders
DD/NDD, ADHD, ID, EP, EPS, ASD
Relevance to Autism

A small subset of patients with Coffin-Lowry syndrome have also presented with autism (Zeniou et al., 2002) or transient autistic behavior (Manouvrier-Hanu et al., 1999), implicating RPS6KA3 as a syndromic ASD gene. On a related note, an ASD case had previously been identified who had also been given a provisional diagnosis of Coffin-Lowry syndrome (Bryson et al., 1988). More recently, a de novo loss-of-function variant in the RPS6KA3 gene was identified in an ASD case from the Simons Simplex Collection (O'Roak et al., 2012).

Molecular Function

This gene encodes a member of the RSK (ribosomal S6 kinase) family of serine/threonine kinases. This kinase contains 2 non-identical kinase catalytic domains and phosphorylates various substrates, including members of the mitogen-activated kinase (MAPK) signalling pathway. The activity of this protein has been implicated in controlling cell growth and differentiation. Mutations in this gene are associated with Coffin-Lowry syndrome (CLS) [MIM:303600], a X-linked mental retardation associated with facial and digital dysmorphisms, progressive skeletal malformations, growth retardation, hearing deficit and paroxysmal movement disorders, as well as with mental retardation, X-linked 19 (MRX19) [MIM:300844], a non-syndromic form of mild-to-moderate mental retardation.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to RPS6KA3 (21 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited A missense mutation in RPS6KA3 (RSK2) responsible for non-specific mental retardation Merienne K , et al. (1999) No -
2 Support Unreported RSK2 missense mutation in two male sibs with an unusually mild form of Coffin-Lowry syndrome Manouvrier-Hanu S , et al. (1999) No ID, ASD
3 Support Unusual splice-site mutations in the RSK2 gene and suggestion of genetic heterogeneity in Coffin-Lowry syndrome Zeniou M , et al. (2002) No -
4 Primary Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations O'Roak BJ , et al. (2012) Yes -
5 Support An Xp22.12 microduplication including RPS6KA3 identified in a family with variably affected intellectual and behavioral disabilities Matsumoto A , et al. (2013) No Epilepsy, ADHD, PDD
6 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No -
7 Support High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing Martnez F , et al. (2016) No ID
8 Support Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior Doan RN , et al. (2016) Yes -
9 Support First report of a Canadian epidemiological study of autistic syndromes Bryson SE , et al. (1988) Yes CLS
10 Support First report of a Canadian epidemiological study of autistic syndromes Bryson SE , et al. (1988) Yes CLS
11 Support - Kaur P et al. (2021) No DD
12 Support - Di Stazio M et al. (2021) No ADHD
13 Support - Pode-Shakked B et al. (2021) No -
14 Support - Mahjani B et al. (2021) Yes -
15 Support - Hu C et al. (2022) Yes -
16 Support - Krgovic D et al. (2022) No Autistic behavior
17 Support - Zhou X et al. (2022) Yes -
18 Support - Spataro N et al. (2023) No -
19 Support - Sanchis-Juan A et al. (2023) No -
20 Support - M Cecilia Poli et al. () No -
21 Support - Ruohao Wu et al. (2024) Yes ADHD
Rare Variants   (19)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
G>T - intergenic_variant - - Unknown 27667684 Doan RN , et al. (2016)
c.61A>G p.Ser21Gly missense_variant Unknown - - 35741772 Hu C et al. (2022)
- - copy_number_loss Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.256A>T p.Lys86Ter stop_gained De novo - - 27620904 Martnez F , et al. (2016)
c.1831A>G p.Met611Val missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.632-2A>C - splice_site_variant Familial Maternal - 34302356 Kaur P et al. (2021)
c.1400T>C p.Leu467Pro missense_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.1631A>G p.Asn544Ser missense_variant Unknown - - 35813072 Krgovic D et al. (2022)
- - copy_number_gain Familial Maternal Multiplex 23985797 Matsumoto A , et al. (2013)
c.135C>T p.Val45%3D missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1106C>G p.Ser369Ter stop_gained De novo - Simplex 22495309 O'Roak BJ , et al. (2012)
c.298A>T p.Lys100Ter stop_gained Unknown Not maternal - 36980980 Spataro N et al. (2023)
c.1269A>T p.Glu423Asp missense_variant Familial Maternal - 38177409 M Cecilia Poli et al. ()
c.832_840del p.Thr278_Ile280del inframe_deletion De novo - Simplex 38764027 Ruohao Wu et al. (2024)
c.889_890del p.Leu298PhefsTer21 frameshift_variant De novo - Simplex 38764027 Ruohao Wu et al. (2024)
c.1152del p.Phe385LeufsTer40 frameshift_variant Familial Maternal - 34580403 Pode-Shakked B et al. (2021)
c.244-7A>G - splice_site_variant De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.566T>A p.Ile189Lys missense_variant Familial Maternal Multiplex 10528858 Manouvrier-Hanu S , et al. (1999)
c.566T>C p.Ile189Thr missense_variant Familial Maternal Extended multiplex 34439726 Di Stazio M et al. (2021)
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, Syndromic

A small subset of patients with Coffin-Lowry syndrome have also presented with autism (Zeniou et al., 2002) or transient autistic behavior (Manouvrier-Hanu et al., 1999), implicating RPS6KA3 as a syndromic ASD gene. On a related note, an ASD case had previously been identified who had also been given a provisional diagnosis of Coffin-Lowry syndrome (Bryson et al., 1988). More recently, a de novo loss-of-function variant in the RPS6KA3 gene was identified in an ASD case from the Simons Simplex Collection (O'Roak et al., 2012).

Score Delta: Score remained at 2S

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.

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
3S
icon
2S

Decreased from 3S to 2S

Description

A small subset of patients with Coffin-Lowry syndrome have also presented with autism (Zeniou et al., 2002) or transient autistic behavior (Manouvrier-Hanu et al., 1999), implicating RPS6KA3 as a syndromic ASD gene. On a related note, an ASD case had previously been identified who had also been given a provisional diagnosis of Coffin-Lowry syndrome (Bryson et al., 1988). More recently, a de novo loss-of-function variant in the RPS6KA3 gene was identified in an ASD case from the Simons Simplex Collection (O'Roak et al., 2012).

10/1/2019
4S
icon
3S

Decreased from 4S to 3S

New Scoring Scheme
Description

A small subset of patients with Coffin-Lowry syndrome have also presented with autism (Zeniou et al., 2002) or transient autistic behavior (Manouvrier-Hanu et al., 1999), implicating RPS6KA3 as a syndromic ASD gene. On a related note, an ASD case had previously been identified who had also been given a provisional diagnosis of Coffin-Lowry syndrome (Bryson et al., 1988). More recently, a de novo loss-of-function variant in the RPS6KA3 gene was identified in an ASD case from the Simons Simplex Collection (O'Roak et al., 2012).

Reports Added
[New Scoring Scheme]
10/1/2016
4S
icon
4S

Decreased from 4S to 4S

Description

A small subset of patients with Coffin-Lowry syndrome have also presented with autism (Zeniou et al., 2002) or transient autistic behavior (Manouvrier-Hanu et al., 1999), implicating RPS6KA3 as a syndromic ASD gene. On a related note, an ASD case had previously been identified who had also been given a provisional diagnosis of Coffin-Lowry syndrome (Bryson et al., 1988). More recently, a de novo loss-of-function variant in the RPS6KA3 gene was identified in an ASD case from the Simons Simplex Collection (O'Roak et al., 2012).

Reports Added
[High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing.2016] [Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior.2016]
7/1/2015
icon
4S

Increased from to 4S

Description

A small subset of patients with Coffin-Lowry syndrome have also presented with autism (Zeniou et al., 2002) or transient autistic behavior (Manouvrier-Hanu et al., 1999), implicating RPS6KA3 as a syndromic ASD gene. On a related note, an ASD case had previously been identified who had also been given a provisional diagnosis of Coffin-Lowry syndrome (Bryson et al., 1988). More recently, a de novo loss-of-function variant in the RPS6KA3 gene was identified in an ASD case from the Simons Simplex Collection (O'Roak et al., 2012).

Krishnan Probability Score

Score 0.57081157872381

Ranking 861/25841 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 0.99990569941684

Ranking 670/18225 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 0.47165109083117

Ranking 391/18665 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 9

Ranking 212/461 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 0.54073152991035

Ranking 283/20870 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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