Human Gene Module / Chromosome 3 / SLC6A1

SLC6A1Solute carrier family 6 (neurotransmitter transporter), member 1

Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
10 / 14
Rare Variants / Common Variants
19 / 3
Aliases
SLC6A1, GABATHG,  GABATR,  GAT1
Associated Syndromes
Tourette syndrome
Genetic Category
Rare Single Gene Mutation, Genetic Association
Chromosome Band
3p25.3
Associated Disorders
ID, ASD
Relevance to Autism

A de novo missense variant in the SLC6A1 gene was identified in an ASD proband from the Simons Simplex Collection (Sanders et al., 2012). This same variant was recently found in two patients (a mother and her female offspring) presenting with myoclonic atonic epilepsy (Carvill et al., 2015). Additional de novo variants in SLC6A1 were identified in patients with myoclonic atonic epilepsy in this report, many of whom also presented with autistic features. This gene was identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of <0.1 (Sanders et al., 2015).

Molecular Function

The SLC6A1 gene encodes a gamma-aminobutyric acid (GABA) transporter, which removes GABA from the synaptic cleft.

Reports related to SLC6A1 (14 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Sanders SJ , et al. (2012) Yes -
2 Support Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
3 Support The contribution of de novo coding mutations to autism spectrum disorder. Iossifov I , et al. (2014) Yes -
4 Recent recommendation Mutations in the GABA Transporter SLC6A1 Cause Epilepsy with Myoclonic-Atonic Seizures. Carvill GL , et al. (2015) No ID, autistic features
5 Support Excess of rare, inherited truncating mutations in autism. Krumm N , et al. (2015) Yes -
6 Recent recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
7 Recent recommendation Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci. Sanders SJ , et al. (2015) Yes -
8 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Lelieveld SH , et al. (2016) No -
9 Support Genome-wide characteristics of de novo mutations in autism. Yuen RK , et al. (2016) Yes -
10 Support Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Stessman HA , et al. (2017) Yes -
11 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. C Yuen RK , et al. (2017) Yes -
12 Positive association SLC6A1 gene involvement in susceptibility to attention-deficit/hyperactivity disorder: A case-control study and gene-environment interaction. Yuan FF , et al. (2017) No -
13 Positive association De Novo Coding Variants Are Strongly Associated with Tourette Disorder. Willsey AJ , et al. (2017) No -
14 Support Genomic diagnosis for children with intellectual disability and/or developmental delay. Bowling KM , et al. (2017) Yes -
Rare Variants   (19)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.863C>T p.Ala288Val missense_variant De novo - Simplex 22495306 Sanders SJ , et al. (2012)
c.1078G>A p.Gly360Ser missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
A>G p.Tyr420Cys missense_variant Familial Paternal - 25363760 De Rubeis S , et al. (2014)
c.723C>A p.Tyr241Ter stop_gained Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
G>T p.Asp165Tyr missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
C>T p.Arg172Cys missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.896G>T p.Gly299Val missense_variant De novo - Simplex 25363768 Iossifov I , et al. (2014)
c.131G>A p.Arg44Gln missense_variant De novo - Simplex 25865495 Carvill GL , et al. (2015)
c.889G>A p.Gly297Arg missense_variant De novo - - 25865495 Carvill GL , et al. (2015)
c.1000G>C p.Ala334Pro missense_variant Familial Maternal - 25865495 Carvill GL , et al. (2015)
c.1369_1370delGG p.Gly457HisfsTer10 frameshift_variant De novo - Simplex 25865495 Carvill GL , et al. (2015)
c.578G>A p.Trp193Ter stop_gained De novo - Simplex 25865495 Carvill GL , et al. (2015)
c.863C>T p.Ala288Val missense_variant Familial Maternal Multi-generational 25865495 Carvill GL , et al. (2015)
c.1648G>A p.Gly550Arg missense_variant De novo - Simplex 25961944 Krumm N , et al. (2015)
c.1024G>A p.Val342Met missense_variant De novo - - 27479843 Lelieveld SH , et al. (2016)
c.1015T>C p.Phe339Leu missense_variant De novo - Simplex 27525107 Yuen RK , et al. (2016)
c.723C>A p.Tyr241Ter stop_gained De novo - Multiplex (suspected twins) 28191889 Stessman HA , et al. (2017)
c.137C>T p.Thr46Met missense_variant De novo - Simplex 28472652 Willsey AJ , et al. (2017)
c.1352A>G p.Asp451Gly missense_variant De novo - - 28554332 Bowling KM , et al. (2017)
Common Variants   (3)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.-215-4116T>C;c.-154-4116T>C - 2_KB_upstream_variant - - - 28442423 Yuan FF , et al. (2017)
c.-215-2020A>G;c.-154-2020A>G - 5_prime_UTR_variant - - - 28442423 Yuan FF , et al. (2017)
c.-216+5824G>T;c.-155+5824G>T - intron_variant - - - 28442423 Yuan FF , et al. (2017)
SFARI Gene score
2

Strong Candidate

A de novo missense variant in the SLC6A1 gene was identified in an ASD proband from the Simons Simplex Collection (Sanders et al., 2012). This same variant was recently found in two patients (a mother and her female offspring) presenting with myoclonic atonic epilepsy (Carvill et al., 2015). Additional de novo variants in SLC6A1 were identified in patients with myoclonic atonic epilepsy in this report, many of whom also presented with autistic features. Two additional de novo missense variants in SLC6A1 that were predicted to be damaging were observed in ASD probands in De Rubeis 2014 and Iossifov 2014. This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). This gene was subsequently identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of <0.1 (Sanders et al., 2015). A de novo nonsense variant in the SLC6A1 gene was identified in a pair of suspected twins from the Autism Genetic Resource Exchange (AGRE) in Stessman et al., 2017.

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.

04-01-2017
2

Initial score established: 2

Description

A de novo missense variant in the SLC6A1 gene was identified in an ASD proband from the Simons Simplex Collection (Sanders et al., 2012). This same variant was recently found in two patients (a mother and her female offspring) presenting with myoclonic atonic epilepsy (Carvill et al., 2015). Additional de novo variants in SLC6A1 were identified in patients with myoclonic atonic epilepsy in this report, many of whom also presented with autistic features. Two additional de novo missense variants in SLC6A1 that were predicted to be damaging were observed in ASD probands in De Rubeis 2014 and Iossifov 2014. This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). This gene was subsequently identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of <0.1 (Sanders et al., 2015). A de novo nonsense variant in the SLC6A1 gene was identified in a pair of suspected twins from the Autism Genetic Resource Exchange (AGRE) in Stessman et al., 2017.

CNVs associated with SLC6A1(1 CNVs)
3p25.3 17 Deletion-Duplication 29  /  86
Animal Models associated with SLC6A1(1 Models)
SLC6A1_1_KO_HM Genetic
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