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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.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
De novo mutations revealed by whole-exome sequencing are strongly associated with autism.
ASD
Positive Association
De Novo Coding Variants Are Strongly Associated with Tourette Disorder.
Tourette syndrome
Positive Association
SLC6A1 gene involvement in susceptibility to attention-deficit/hyperactivity disorder: A case-control study and gene-environment interaction.
ADHD
Support
Excess of rare, inherited truncating mutations in autism.
ASD
Support
Using medical exome sequencing to identify the causes of neurodevelopmental disorders: experience of two clinical units and 216 patients.
ID, epilepsy/seizures
Support
A missense mutation in SLC6A1 associated with Lennox-Gastaut syndrome impairs GABA transporter 1 protein trafficking and function.
DD, ID, epilepsy/seizures
Support
The contribution of de novo coding mutations to autism spectrum disorder.
ASD
Support
Genomic diagnosis for children with intellectual disability and/or developmental delay.
ASD, ID, epilepsy/seizures
Support
The Clinical and Genetic Features of Co-occurring Epilepsy and Autism Spectrum Disorder in Chinese Children.
ASD, epilepsy/seizures
Support
Synaptic, transcriptional and chromatin genes disrupted in autism.
ASD
Support
Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder.
ASD
Support
Neurological Diseases With Autism Spectrum Disorder: Role of ASD Risk Genes.
ASD
ID, epilepsy/seizures
Support
Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.
ASD
Support
SLC6A1 variants identified in epilepsy patients reduce -aminobutyric acid transport.
Epilepsy/seizures
ID, ASD
Support
Genome-wide characteristics of de novo mutations in autism.
ASD
Support
Language Regression in an Atypical SLC6A1 Mutation.
ASD, epilepsy/seizures
Language delay, regression
Support
Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder.
ASD
Support
Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability.
ID
Support
Phenotypic consequences of gene disruption by a balanced de novo translocation involving SLC6A1 and NAA15.
DD, epilepsy/seizures
Support
Clinical utility of multigene panel testing in adults with epilepsy and intellectual disability.
ID, epilepsy/seizures
ADHD, behavioral problems
Recent Recommendation
Defining the phenotypic spectrum of SLC6A1 mutations.
Epilepsy/seizures, ID
ASD or autistic features
Recent Recommendation
Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci.
ASD
Recent Recommendation
Low load for disruptive mutations in autism genes and their biased transmission.
ASD
Recent Recommendation
Mutations in the GABA Transporter SLC6A1 Cause Epilepsy with Myoclonic-Atonic Seizures.
Epilepsy/seizures
ID, autistic features

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN714R001 
 missense_variant 
 c.863C>T 
 p.Ala288Val 
 De novo 
 NA 
 Simplex 
 GEN714R002 
 missense_variant 
 c.131G>A 
 p.Arg44Gln 
 De novo 
 NA 
 Simplex 
 GEN714R003 
 missense_variant 
 c.889G>A 
 p.Gly297Arg 
 De novo 
 NA 
  
 GEN714R004 
 missense_variant 
 c.1000G>C 
 p.Ala334Pro 
 Familial 
 Maternal 
  
 GEN714R005 
 frameshift_variant 
 c.1369_1370del 
 p.Gly457HisfsTer10 
 De novo 
 NA 
 Simplex 
 GEN714R006 
 stop_gained 
 c.578G>A 
 p.Trp193Ter 
 De novo 
 NA 
 Simplex 
 GEN714R007 
 missense_variant 
 c.863C>T 
 p.Ala288Val 
 Familial 
 Maternal 
 Multi-generational 
 GEN714R008 
 copy_number_loss 
  
  
 De novo 
 NA 
 Simplex 
 GEN714R009 
 missense_variant 
 c.1648G>A 
 p.Gly550Arg 
 De novo 
 NA 
 Simplex 
 GEN714R010 
 missense_variant 
 c.1078G>A 
 p.Gly360Ser 
 De novo 
 NA 
  
 GEN714R011 
 missense_variant 
 c.896G>T 
 p.Gly299Val 
 De novo 
 NA 
 Simplex 
 GEN714R012 
 missense_variant 
 c.1793A>G 
 p.Tyr598Cys 
 Familial 
 Paternal 
  
 GEN714R013 
 stop_gained 
 c.723C>A 
 p.Tyr241Ter 
 Unknown 
  
 Unknown 
 GEN714R014 
 missense_variant 
 c.493G>T 
 p.Asp165Tyr 
 Unknown 
  
 Unknown 
 GEN714R015 
 missense_variant 
 c.514C>T 
 p.Arg172Cys 
 Unknown 
  
 Unknown 
 GEN714R016 
 missense_variant 
 c.1024G>A 
 p.Val342Met 
 De novo 
 NA 
  
 GEN714R017 
 missense_variant 
 c.1015T>C 
 p.Phe339Leu 
 De novo 
 NA 
 Simplex 
 GEN714R018 
 stop_gained 
 c.723C>A 
 p.Tyr241Ter 
 De novo 
 NA 
 Multiplex (suspected twins) 
 GEN714R019 
 missense_variant 
 c.137C>T 
 p.Thr46Met 
 De novo 
 NA 
 Simplex 
 GEN714R020 
 missense_variant 
 c.1352A>G 
 p.Asp451Gly 
 De novo 
 NA 
  
 GEN714R021 
 missense_variant 
 c.223G>A 
 p.Gly75Arg 
 De novo 
 NA 
  
 GEN714R022 
 frameshift_variant 
 c.638dup 
 p.Leu214ThrfsTer68 
 De novo 
 NA 
 Simplex 
 GEN714R023 
 missense_variant 
 c.223G>A 
 p.Gly75Arg 
 De novo 
 NA 
  
 GEN714R024 
 missense_variant 
 c.419A>G 
 p.Tyr140Cys 
 De novo 
 NA 
 Simplex 
 GEN714R025 
 missense_variant 
 c.434C>T 
 p.Ser145Phe 
 De novo 
 NA 
 Simplex 
 GEN714R026 
 missense_variant 
 c.695G>T 
 p.Gly232Val 
 De novo 
 NA 
 Simplex 
 GEN714R027 
 missense_variant 
 c.695G>T 
 p.Gly232Val 
 Familial 
 Maternal 
 Multi-generational 
 GEN714R028 
 missense_variant 
 c.809T>C 
 p.Phe270Ser 
 De novo 
 NA 
 Simplex 
 GEN714R029 
 missense_variant 
 c.863C>T 
 p.Ala288Val 
 De novo 
 NA 
 Simplex 
 GEN714R030 
 missense_variant 
 c.863C>T 
 p.Ala288Val 
 Unknown 
  
 Not simplex 
 GEN714R031 
 inframe_deletion 
 c.881_883del 
 p.Ser294del 
 De novo 
 NA 
 Simplex 
 GEN714R032 
 stop_gained 
 c.987C>A 
 p.Cys329Ter 
 De novo 
 NA 
 Simplex 
 GEN714R033 
 missense_variant 
 c.1024G>A 
 p.Val342Met 
 Familial 
 Paternal 
 Multi-generational 
 GEN714R034 
 missense_variant 
 c.1024G>A 
 p.Val342Met 
 De novo 
 NA 
 Simplex 
 GEN714R035 
 missense_variant 
 c.1024G>A 
 p.Val342Met 
 De novo 
 NA 
 Simplex 
 GEN714R036 
 missense_variant 
 c.1024G>A 
 p.Val342Met 
 De novo 
 NA 
 Not simplex 
 GEN714R037 
 missense_variant 
 c.1070C>T 
 p.Ala357Val 
 De novo 
 NA 
 Simplex 
 GEN714R038 
 missense_variant 
 c.1084G>A 
 p.Gly362Arg 
 Unknown 
  
 Unknown 
 GEN714R039 
 missense_variant 
 c.1084G>A 
 p.Gly362Arg 
 Familial 
 Maternal 
 Simplex 
 GEN714R040 
 missense_variant 
 c.1155C>G 
 p.Phe385Leu 
 De novo 
 NA 
 Simplex 
 GEN714R041 
 stop_gained 
 c.*76A>T 
  
 De novo 
 NA 
 Simplex 
 GEN714R042 
 missense_variant 
 c.*111C>G 
  
 De novo 
 NA 
 Simplex 
 GEN714R043 
 missense_variant 
 c.*265G>A 
  
 De novo 
 NA 
 Simplex 
 GEN714R044 
 stop_gained 
 c.1600C>T 
 p.Gln534Ter 
 De novo 
 NA 
 Simplex 
 GEN714R045 
 splice_site_variant 
 c.850-2A>G 
  
 De novo 
 NA 
 Unknown 
 GEN714R046 
 splice_site_variant 
 c.1528-1G>C 
  
 De novo 
 NA 
  
 GEN714R047 
 translocation 
  
  
 De novo 
 NA 
  
 GEN714R048 
 missense_variant 
 c.302A>G 
 p.Glu101Gly 
 De novo 
 NA 
  
 GEN714R049 
 missense_variant 
 c.281G>A 
 p.Gly94Glu 
 Unknown 
  
  
 GEN714R050 
 missense_variant 
 c.703T>C 
 p.Trp235Arg 
 Unknown 
  
  
 GEN714R051 
 inframe_deletion 
 c.1349_1351del 
 p.Phe450_Asp451delinsTyr 
 De novo 
 NA 
  
 GEN714R052 
 missense_variant 
 c.1334A>G 
 p.Tyr445Cys 
 Unknown 
  
  
 GEN714R053 
 stop_gained 
 c.*221G>A 
  
 Unknown 
  
  
 GEN714R054 
 missense_variant 
 c.1648G>A 
 p.Gly550Arg 
 Unknown 
  
  
 GEN714R055 
 splice_site_variant 
 c.714+1G>A 
  
 De novo 
 NA 
  
 GEN714R056 
 missense_variant 
 c.995T>G 
 p.Met332Arg 
 De novo 
 NA 
  
 GEN714R057 
 intron_variant 
 c.1848-9A>G 
 p.? 
 De novo 
 NA 
  
 GEN714R058 
 missense_variant 
 c.700G>A 
 p.Gly234Ser 
 Unknown 
 Not paternal 
 Simplex 
 GEN714R059 
 missense_variant 
 c.1460T>C 
 p.Met487Thr 
 De novo 
 NA 
  
 GEN714R060 
 missense_variant 
 c.752T>C 
 p.Ile251Thr 
 De novo 
 NA 
 Simplex 

Common

Variant ID
Polymorphism
SNP ID
Allele Change
Residue Change
Population Origin
Population Stage
Author, Year
 GEN714C001 
 2_KB_upstream_variant 
 rs2944366 
 c.-215-4116T>C;c.-154-4116T>C 
  
 302 Chinese ADHD patients (244 male, 58 female; mean age 8.44 1.72 years) and 411 ethnically-matched controls (318 male, 93 female, mean age 8.22 2.13 years) 
 Discovery 
 GEN714C002 
 5_prime_UTR_variant 
 rs1170695 
 c.-215-2020A>G;c.-154-2020A>G 
  
 302 Chinese ADHD patients (244 male, 58 female; mean age 8.44 1.72 years) and 411 ethnically-matched controls (318 male, 93 female, mean age 8.22 2.13 years) 
 Discovery 
 GEN714C003 
 intron_variant 
 rs9990174 
 c.-216+5824G>T;c.-155+5824G>T 
  
 302 Chinese ADHD patients (244 male, 58 female; mean age 8.44 1.72 years) 
 Discovery 
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
3
Deletion-Duplication
 19
 
3
Deletion
 1
 
3
Deletion
 1
 
3
Duplication
 1
 
3
Duplication
 1
 
3
Duplication
 1
 
3
Duplication
 2
 
3
Deletion
 2
 

Model Summary

Slc6a1 null mice have impaired learning and memory of contextual fear conditioning, spatial learning that correlates with reduced theta burst stimulation induced LTP in the hippocampus.

References

Type
Title
Author, Year
Primary
GABA transporter-1 activity modulates hippocampal theta oscillation and theta burst stimulation-induced long-term potentiation.

M_SLC6A1_1_KO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: A neomycin resistance cassette replaced exon 2 and 3 of the Slc6a1 gene to inactivate the gene. Following germline transmission heterozygous mice were backcrossed to C57BL/6 mice and intercrossed to generate homozygous knockouts.
Allele Type: Targeted(knockout)
Strain of Origin:
Genetic Background: C57BL/6
ES Cell Line: CJ7
Mutant ES Cell Line:
Model Source: PMID: 20016099

M_SLC6A1_1_KO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
General locomotor activity: ambulatory activity1
Increased
Description: Slc6a1 KO mice display increased locomotor activity
 General observations
 3-5 months
Event related oscillations (eros) in electroencephalography (eeg)1
Decreased
Description: There is a significant decrease in the frequency of theta oscillation in vivo EEG recordings, during REM sleep and exploratory activity in a novel environment, in Slc6a1 KO mice. No change in the peak power in theta band during REM sleep or exploration was noted
 Electroencephalogram (eeg)
 Adult
Decay kinetics of evoked post synaptic currents1
Increased
Description: IPScs are prolonged and display longer decay tune ub tge Slc6a1 KO hippocampal slices
 Whole-cell patch clamp
 6- 10 weeks
Tonic currents through extrasynaptic receptors1
Increased
Description: GABA induced tonic inhibitory currents are larger in Slc6a1 KO mice, which is expected due to impaired GABA uptake because of loss of GABA transporter Slc6a1
 Whole-cell patch clamp
 6- 10 weeks
Synaptic plasticity: hippocampal ltp1
Decreased
Description: Theta burst stimulation does not induce LTP in the hippocampal slices of Slc6a1 KO mice, unlike in WT slices. Authors note that high frequency stimulation induces normal LTP in the Slc6a1 KO slices
 Field potential recordings
 6- 10 weeks
Spatial learning1
Decreased
Description: Slc6a1 KO mice display longer latency in finding the platform during the training sessions of the Morris water maze test
 Morris water maze test
 3-5 months
Cued or contextual fear conditioning: passive avoidance1
Decreased
Description: Slc6a1 KO mice display reduced latency to enter the dark compartment , where they had previously received a footshock, compared to wild type controls
 Passive avoidance test
 3-5 months
Cued or contextual fear conditioning: memory of context1
Decreased
Description: Slc6a1 KO mice display reduced freezing when reintroduced to the same context where they received a footshock indicating impaired contextual memory
 Fear conditioning test
 3-5 months
Spatial reference memory1
Decreased
Description: Slc6a1 KO mice display a significantly lower preference for the target quadrant, in the probe trial, compared to wild type controls
 Morris water maze test
 3-5 months
Swimming ability1
 No change
 Morris water maze test
 3-5 months
Hippocampal morphology1
 No change
 Histology
 Adult
Neuroreceptor levels: gaba-r: gabaa1
 No change
 Western blot
 Adult
Neuroreceptor levels: glutamate receptors: ampa receptors1
 No change
 Western blot
 Adult
Neuroreceptor levels: glutamate receptors: nmda receptors1
 No change
 Western blot
 Adult
Presynaptic function: paired-pulse facilitation1
 No change
 Whole-cell patch clamp
 6- 10 weeks
Synaptic plasticity: hippocampal ltd1
 No change
 Field potential recordings
 6- 10 weeks
Synaptic transmission: excitatory1
 No change
 Whole-cell patch clamp
 6- 10 weeks
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Emotion, Immune response, Maternal behavior, Molecular profile, Physiological parameters, Repetitive behavior, Seizure, Sensory, Social behavior

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