Human Gene Module / Chromosome X / SLC6A8

SLC6A8solute carrier family 6 (neurotransmitter transporter, creatine), member 8

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
13 / 26
Rare Variants / Common Variants
31 / 0
Aliases
SLC6A8, CT1,  CRTR,  MGC87396
Associated Syndromes
Cerebral creatine deficiency syndrome 1, Cerebral creatine deficiency syndrome 1, ASD, DD,
Chromosome Band
Xq28
Associated Disorders
DD/NDD, ID, EP, EPS, ASD
Relevance to Autism

This gene has been identified with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. As well, rare variants in the SLC6A8 gene have been identified with autism (Po-Argelles et al., 2006).

Molecular Function

The encoded protein has creatine:sodium symporter activity.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome Informatics
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to SLC6A8 (26 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited X-linked creatine-transporter gene (SLC6A8) defect: a new creatine-deficiency syndrome Salomons GS , et al. (2001) No -
2 Primary X-Linked creatine transporter deficiency in two patients with severe mental retardation and autism Po-Argelles P , et al. (2006) Yes MR, epilepsy, dystonia
3 Recent Recommendation Overexpression of wild-type creatine transporter (SLC6A8) restores creatine uptake in primary SLC6A8-deficient fibroblasts Rosenberg EH , et al. (2006) No -
4 Support Hybridisation-based resequencing of 17 X-linked intellectual disability genes in 135 patients reveals novel mutations in ATRX, SLC6A8 and PQBP1 Jensen LR , et al. (2011) No -
5 Support Diagnostic exome sequencing in persons with severe intellectual disability de Ligt J , et al. (2012) No Epilepsy, ASD
6 Support Analysis of the chromosome X exome in patients with autism spectrum disorders identified novel candidate genes, including TMLHE Nava C , et al. (2012) Yes ID
7 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
8 Support Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms D'Gama AM , et al. (2015) Yes -
9 Support Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders Reuter MS , et al. (2017) No ID
10 Support Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders Li J , et al. (2017) Yes -
11 Support A novel SLC6A8 mutation associated with intellectual disabilities in a Chinese family exhibiting creatine transporter deficiency: case report Wang Q , et al. (2018) No DD, ID, epilepsy/seizures, autistic features
12 Support Neurological Diseases With Autism Spectrum Disorder: Role of ASD Risk Genes Xiong J , et al. (2019) Yes Epilepsy/seizures, Cerebral creatine deficiency sy
13 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
14 Support Targeted Next-Generation Sequencing in Patients with Suggestive X-Linked Intellectual Disability Ibarluzea N , et al. (2020) No -
15 Support - Abe-Hatano C et al. (2021) No -
16 Support - Mir A et al. (2021) Yes -
17 Support - Chen S et al. (2021) Yes Epilepsy/seizures
18 Support - Morey K et al. (2022) Yes -
19 Support - Stenshorne I et al. (2022) No -
20 Support - Zhou X et al. (2022) Yes -
21 Support - Hu C et al. (2023) Yes -
22 Support - Bartolomaeus T et al. (2023) No -
23 Support - Riquin K et al. (2023) No -
24 Support - Balasar et al. (2023) Yes -
25 Support - Léa Broca-Brisson et al. (2023) No -
26 Support - Axel Schmidt et al. (2024) No ASD, ID
Rare Variants   (31)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1169C>T p.Pro390Leu missense_variant - - - 21267006 Jensen LR , et al. (2011)
c.1430C>T p.Ser477Leu missense_variant - - - 21267006 Jensen LR , et al. (2011)
- - copy_number_loss Familial Maternal Simplex 37495270 Riquin K et al. (2023)
c.263-6C>T - splice_region_variant Familial Paternal - 37007974 Hu C et al. (2023)
c.442_444del p.Tyr148del inframe_deletion De novo - - 35982159 Zhou X et al. (2022)
c.1540C>T p.Arg514Ter stop_gained De novo - Simplex 35169411 Morey K et al. (2022)
c.1540C>T p.Arg514Ter stop_gained Familial Maternal - 34800434 Chen S et al. (2021)
c.913-1G>T - splice_site_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.947C>T p.Ser316Phe missense_variant De novo - - 31452935 Feliciano P et al. (2019)
c.1540C>T p.Arg514Ter stop_gained Familial Maternal - 31031587 Xiong J , et al. (2019)
c.1196C>A p.Ala399Asp missense_variant De novo - - 35979408 Stenshorne I et al. (2022)
c.1661C>T p.Pro554Leu missense_variant Unknown - - 39039281 Axel Schmidt et al. (2024)
c.1405G>C p.Val469Leu missense_variant Familial Maternal - 37007974 Hu C et al. (2023)
c.1139C>A p.Ser380Ter missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.1006_1008del p.Asn336del inframe_deletion De novo - - 23033978 de Ligt J , et al. (2012)
c.942_944del p.Phe315del inframe_deletion De novo - Simplex 35982159 Zhou X et al. (2022)
c.1649C>G p.Thr550Ser missense_variant Unknown - Multiplex 23092983 Nava C , et al. (2012)
c.497C>T p.Thr166Met missense_variant Unknown - Multiplex 37524782 Balasar et al. (2023)
1215+TTC(delTTC) -405 inframe_deletion De novo - Simplex 25363768 Iossifov I et al. (2014)
c.1494C>T p.Tyr498= synonymous_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.940_942delTTC p.Phe315del inframe_deletion Unknown - - 39039281 Axel Schmidt et al. (2024)
c.740_745del p.Tyr247_Phe248del inframe_deletion Familial Maternal - 34797406 Mir A et al. (2021)
c.1181C>A p.Thr394Lys missense_variant Familial Maternal Multiplex 30400883 Wang Q , et al. (2018)
c.644A>G p.Glu215Gly missense_variant Familial Maternal Simplex 28097321 Reuter MS , et al. (2017)
c.974_975del p.Thr325SerfsTer139 frameshift_variant Unknown - - 39039281 Axel Schmidt et al. (2024)
c.1145C>T p.Pro382Leu missense_variant Familial Maternal Unknown 33624935 Abe-Hatano C et al. (2021)
c.205_206del p.Ala69ArgfsTer119 frameshift_variant Unknown - Unknown 26637798 D'Gama AM , et al. (2015)
c.644A>G p.Glu215Gly missense_variant Familial Maternal Simplex 37460657 Bartolomaeus T et al. (2023)
c.1361_1362+1del - inframe_deletion Familial Maternal Multi-generational 31906484 Ibarluzea N , et al. (2020)
c.1192_1194del p.Phe398del inframe_deletion Familial Maternal Simplex 16601898 Po-Argelles P , et al. (2006)
c.878_879del p.Leu293GlnfsTer3 frameshift_variant Familial Maternal Simplex 16601898 Po-Argelles P , et al. (2006)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Rare variants without large case-control study. Poo-Arguelles et al., 2006 report rare deleterious variants in two kids with intellectual disability with autism symptoms. Newmeyer et al. found one novel variant from 100 subjects. Mutations in the SLC6A8 gene are responsible for cerebral creatine deficiency syndrome-1 (CCDS1; OMIM 300352).

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

Rare variants without large case-control study. Poo-Arguelles et al., 2006 report rare deleterious variants in two kids with intellectual disability with autism symptoms. Newmeyer et al. found one novel variant from 100 subjects. Mutations in the SLC6A8 gene are responsible for cerebral creatine deficiency syndrome-1 (CCDS1; OMIM 300352).

1/1/2021
3
icon
3

Decreased from 3 to 3

Description

Rare variants without large case-control study. Poo-Arguelles et al., 2006 report rare deleterious variants in two kids with intellectual disability with autism symptoms. Newmeyer et al. found one novel variant from 100 subjects. Mutations in the SLC6A8 gene are responsible for cerebral creatine deficiency syndrome-1 (CCDS1; OMIM 300352).

Reports Added
[Whole genome sequencing of 45 Japanese patients with intellectual disability2021]
1/1/2020
3
icon
3

Decreased from 3 to 3

Description

Rare variants without large case-control study. Poo-Arguelles et al., 2006 report rare deleterious variants in two kids with intellectual disability with autism symptoms. Newmeyer et al. found one novel variant from 100 subjects. Mutations in the SLC6A8 gene are responsible for cerebral creatine deficiency syndrome-1 (CCDS1; OMIM 300352).

Reports Added
[Targeted Next-Generation Sequencing in Patients with Suggestive X-Linked Intellectual Disability.2020]
10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Rare variants without large case-control study. Poo-Arguelles et al., 2006 report rare deleterious variants in two kids with intellectual disability with autism symptoms. Newmeyer et al. found one novel variant from 100 subjects. Mutations in the SLC6A8 gene are responsible for cerebral creatine deficiency syndrome-1 (CCDS1; OMIM 300352).

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

Decreased from 4 to 4

Description

Rare variants without large case-control study. Poo-Arguelles et al., 2006 report rare deleterious variants in two kids with intellectual disability with autism symptoms. Newmeyer et al. found one novel variant from 100 subjects. Mutations in the SLC6A8 gene are responsible for cerebral creatine deficiency syndrome-1 (CCDS1; OMIM 300352).

Reports Added
[Neurological Diseases With Autism Spectrum Disorder: Role of ASD Risk Genes.2019]
10/1/2018
4
icon
4

Decreased from 4 to 4

Description

Rare variants without large case-control study. Poo-Arguelles et al., 2006 report rare deleterious variants in two kids with intellectual disability with autism symptoms. Newmeyer et al. found one novel variant from 100 subjects. Mutations in the SLC6A8 gene are responsible for cerebral creatine deficiency syndrome-1 (CCDS1; OMIM 300352).

Reports Added
[A novel SLC6A8 mutation associated with intellectual disabilities in a Chinese family exhibiting creatine transporter deficiency: case report.2018]
10/1/2017
4
icon
4

Decreased from 4 to 4

Description

Rare variants without large case-control study. Poo-Arguelles et al., 2006 report rare deleterious variants in two kids with intellectual disability with autism symptoms. Newmeyer et al. found one novel variant from 100 subjects. Mutations in the SLC6A8 gene are responsible for cerebral creatine deficiency syndrome-1 (CCDS1; OMIM 300352).

Reports Added
[Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders.2017]
1/1/2017
4
icon
4

Decreased from 4 to 4

Description

Rare variants without large case-control study. Poo-Arguelles et al., 2006 report rare deleterious variants in two kids with intellectual disability with autism symptoms. Newmeyer et al. found one novel variant from 100 subjects. Mutations in the SLC6A8 gene are responsible for cerebral creatine deficiency syndrome-1 (CCDS1; OMIM 300352).

Reports Added
[Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders.2017]
1/1/2016
4
icon
4

Decreased from 4 to 4

Description

Rare variants without large case-control study. Poo-Arguelles et al., 2006 report rare deleterious variants in two kids with intellectual disability with autism symptoms. Newmeyer et al. found one novel variant from 100 subjects. Mutations in the SLC6A8 gene are responsible for cerebral creatine deficiency syndrome-1 (CCDS1; OMIM 300352).

Reports Added
[X-Linked creatine transporter deficiency in two patients with severe mental retardation and autism.2006] [Analysis of the chromosome X exome in patients with autism spectrum disorders identified novel candidate genes, including TMLHE.2012] [Hybridisation-based resequencing of 17 X-linked intellectual disability genes in 135 patients reveals novel mutations in ATRX, SLC6A8 and PQBP1.2011] [Diagnostic exome sequencing in persons with severe intellectual disability.2012] [X-linked creatine-transporter gene (SLC6A8) defect: a new creatine-deficiency syndrome.2001] [Overexpression of wild-type creatine transporter (SLC6A8) restores creatine uptake in primary SLC6A8-deficient fibroblasts.2006] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms.2015]
7/1/2014
No data
icon
4

Increased from No data to 4

Description

Rare variants without large case-control study. Poo-Arguelles et al., 2006 report rare deleterious variants in two kids with intellectual disability with autism symptoms. Newmeyer et al. found one novel variant from 100 subjects.

4/1/2014
No data
icon
4

Increased from No data to 4

Description

Rare variants without large case-control study. Poo-Arguelles et al., 2006 report rare deleterious variants in two kids with intellectual disability with autism symptoms. Newmeyer et al. found one novel variant from 100 subjects.

Krishnan Probability Score

Score 0.44489187112136

Ranking 15671/25841 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 0.99188960273256

Ranking 1718/18225 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 0.47112140413575

Ranking 390/18665 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 291/461 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 -0.61587718561455

Ranking 19970/20870 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
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
TPRA1 Transmembrane protein adipocyte-associated 1 Human Protein Binding 131601 Q86W33-2
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