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
6 / 19
Rare Variants / Common Variants
17 / 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.

SFARI Genomic Platforms
Reports related to RPS6KA3 (20 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 - et al. () No -
Rare Variants   (17)
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.1269A>T p.Glu423Asp missense_variant Familial Maternal - 38177409 et al. ()
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.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

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.

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).

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.
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
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).
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.
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.
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