Human Gene Module / Chromosome 3 / SLC6A1

SLC6A1Solute carrier family 6 (neurotransmitter transporter), member 1

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
26 / 55
Rare Variants / Common Variants
157 / 3
EAGLE Score
31.15
Strong Learn More
Aliases
SLC6A1, GABATHG,  GABATR,  GAT1
Associated Syndromes
Tourette syndrome
Chromosome Band
3p25.3
Associated Disorders
DD/NDD, ADHD, ID, EPS, ASD
Genetic Category
Rare Single Gene Mutation, Syndromic, Genetic Association
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). Four de novo missense variants that were predicted to be deleterious (defined as having an MPC score 2) were identified in the SLC6A1 gene in ASD probands from the Autism Sequencing Consortium in Satterstrom et al., 2020; subsequent TADA analysis of de novo variants from the Simons Simplex Collection and the Autism Sequencing Consortium and protein-truncating variants from iPSYCH in this report identified SLC6A1 as a candidate gene with a false discovery rate (FDR) 0.01. A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified SLC6A1 as a gene reaching exome-wide significance (P < 2.5E-06). Phenotypic evaluation of 34 individuals (30 novel, 4 previously published) with SLC6A1 mutations in Johannesen et al., 2018 demonstrated that impaired cognitive development (intellectual disability or learning disability) and epilepsy were the most common phenotypes; in addition, behavioral problems were frequently observed in individuals in this study, with eight patients presenting with ASD or autistic features. Mermer et al., 2021 experimentally assessed twenty-two SLC6A1 variants identified in patients with a broad spectrum of phenotypes, including SLC6A1 missense variants identified in ASD probands, and found that partial or complete loss of function (characterized by reduced GABA uptake and surface expression) was a common disease mechanism regardless of disease phenotype.

Molecular Function

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

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 SLC6A1 (55 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 -
15 Support Using medical exome sequencing to identify the causes of neurodevelopmental disorders: Experience of 2 clinical units and 216 patients Chrot E , et al. (2017) No -
16 Recent Recommendation Defining the phenotypic spectrum of SLC6A1 mutations Johannesen KM , et al. (2018) No ASD or autistic features
17 Support Phenotypic consequences of gene disruption by a balanced de novo translocation involving SLC6A1 and NAA15 Pesz K , et al. (2018) No -
18 Support Language Regression in an Atypical SLC6A1 Mutation Islam MP , et al. (2018) Yes Language delay, regression
19 Support SLC6A1 variants identified in epilepsy patients reduce ?-aminobutyric acid transport Mattison KA , et al. (2018) No ID, ASD
20 Support Neurological Diseases With Autism Spectrum Disorder: Role of ASD Risk Genes Xiong J , et al. (2019) Yes ID, epilepsy/seizures
21 Support The Clinical and Genetic Features of Co-occurring Epilepsy and Autism Spectrum Disorder in Chinese Children Long S , et al. (2019) Yes -
22 Support A missense mutation in SLC6A1 associated with Lennox-Gastaut syndrome impairs GABA transporter 1 protein trafficking and function Cai K , et al. (2019) No -
23 Support Clinical utility of multigene panel testing in adults with epilepsy and intellectual disability Borlot F , et al. (2019) No ADHD, behavioral problems
24 Support Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder Munnich A , et al. (2019) Yes -
25 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
26 Support Excess of de novo variants in genes involved in chromatin remodelling in patients with marfanoid habitus and intellectual disability Chevarin M et al. (2020) No Marfanoid habitus
27 Support Endoplasmic reticulum retention and degradation of a mutation in SLC6A1 associated with epilepsy and autism Wang J et al. (2020) Yes DD, ID
28 Support Phenotypic and genetic spectrum of epilepsy with myoclonic atonic seizures Tang S et al. (2020) No ASD
29 Support SLC6A1 G443D associated with developmental delay and epilepsy Devries S et al. (2020) Yes -
30 Support Clinical and genetic characteristics of patients with Doose syndrome Hinokuma N et al. (2020) No DD, ID
31 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes ID
32 Support - Alonso-Gonzalez A et al. (2021) Yes -
33 Support - Brunet T et al. (2021) No -
34 Support - Poliquin S et al. (2021) No -
35 Recent Recommendation - Kahen A et al. (2021) No ASD, ADHD, ID
36 Recent Recommendation - Mermer F et al. (2021) Yes -
37 Support - Qaiser F et al. (2021) Yes -
38 Support - Aguilera C et al. (2021) No Stereotypy
39 Support - Chen S et al. (2021) Yes Epilepsy/seizures
40 Support - Brea-Fernández AJ et al. (2022) No -
41 Support - Chuan Z et al. (2022) No -
42 Support - Bain JM et al. (2022) No ASD, ADHD
43 Support - Nwosu G et al. (2022) No ASD, DD, ID
44 Support - Zhou X et al. (2022) Yes -
45 Support - Verhoeven W et al. (2022) Yes -
46 Support - Piniella D et al. (2023) Yes -
47 Support - Kasture AS et al. (2023) No -
48 Support - Goodspeed K et al. (2023) No ASD
49 Support - Miyake N et al. (2023) Yes -
50 Support - Caputo D et al. (2023) No ID
51 Support - Kassabian B et al. (2023) No ASD or autistic features, ADHD, BPD, stereotypy
52 Support - Sanchis-Juan A et al. (2023) No ID
53 Support - Johannesen KM et al. (2023) No ASD or autistic features, epilepsy/seizures
54 Support - et al. () No Stereotypy
55 Support - et al. () No -
Rare Variants   (157)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - translocation De novo - - 29621621 Pesz K , et al. (2018)
c.*221G>A - stop_gained Unknown - - 30132828 Mattison KA , et al. (2018)
- - copy_number_loss De novo - Simplex 25865495 Carvill GL , et al. (2015)
c.714+1G>A - splice_site_variant De novo - - 34800434 Chen S et al. (2021)
c.1696-1G>A - splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
c.714+1G>A - splice_site_variant De novo - - 31031587 Xiong J , et al. (2019)
c.695G>T p.Gly232Val missense_variant De novo - Simplex 37700749 et al. ()
c.1595G>A p.Trp532Ter stop_gained Unknown - - 34006619 Kahen A et al. (2021)
c.1070C>T p.Ala357Val missense_variant De novo - Simplex 37700749 et al. ()
c.131G>A p.Arg44Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.154G>A p.Asp52Asn missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.223G>C p.Gly75Arg missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.*76A>T - stop_gained De novo - Simplex 29315614 Johannesen KM , et al. (2018)
c.1531G>A p.Val511Met missense_variant Familial Paternal - 38008000 et al. ()
c.419A>G p.Tyr140Cys missense_variant De novo - - 32469098 Tang S et al. (2020)
c.478C>T p.Pro160Ser missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.607G>A p.Gly203Arg missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.779C>T p.Thr260Met missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.820C>T p.Pro274Ser missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.863C>T p.Ala288Val missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.889G>A p.Gly297Arg missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.913G>A p.Ala305Thr missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.919G>A p.Gly307Arg missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.995T>G p.Met332Arg missense_variant De novo - - 34800434 Chen S et al. (2021)
c.863C>T p.Ala288Val missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.131G>A p.Arg44Gln missense_variant Unknown - - 34006619 Kahen A et al. (2021)
c.1155C>G p.Phe385Leu missense_variant De novo - - 32469098 Tang S et al. (2020)
c.1009G>A p.Val337Ile missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1070C>T p.Ala357Val missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1178G>T p.Gly393Val missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1229A>G p.Asp410Gly missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1436G>A p.Arg479Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1436G>C p.Arg479Pro missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1559C>T p.Thr520Met missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1256G>A p.Arg419His missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.913G>A p.Ala305Thr missense_variant Unknown - - 34006619 Kahen A et al. (2021)
c.223G>A p.Gly75Arg missense_variant De novo - - 28708303 Chrot E , et al. (2017)
c.1084G>A p.Gly362Arg missense_variant Unknown - - 34006619 Kahen A et al. (2021)
c.995T>G p.Met332Arg missense_variant De novo - - 31031587 Xiong J , et al. (2019)
c.1531G>A p.Val511Met missense_variant Familial - - 34006619 Kahen A et al. (2021)
c.871C>T p.Gln291Ter stop_gained De novo - Simplex 34006619 Kahen A et al. (2021)
c.1695+1G>A - splice_site_variant De novo - Simplex 34006619 Kahen A et al. (2021)
- p.Gly297Arg missense_variant Unknown - Multiplex 34622207 Qaiser F et al. (2021)
c.302A>G p.Glu101Gly missense_variant De novo - - 29961511 Islam MP , et al. (2018)
c.1528-1G>C - splice_site_variant De novo - - 29315614 Johannesen KM , et al. (2018)
NM_001348250.1:c.1848A>G - intron_variant De novo - - 31139143 Long S , et al. (2019)
c.1460T>C p.Met487Thr missense_variant De novo - - 31273778 Borlot F , et al. (2019)
c.1328G>A p.Gly443Asp missense_variant De novo - - 32660967 Devries S et al. (2020)
c.889G>A p.Gly297Arg missense_variant De novo - - 34653234 Aguilera C et al. (2021)
c.881_883del p.Phe294del inframe_deletion Unknown - - 34006619 Kahen A et al. (2021)
c.418_420del p.Tyr140del inframe_deletion Unknown - - 35571021 Chuan Z et al. (2022)
c.889G>A p.Gly297Arg missense_variant De novo - - 25865495 Carvill GL , et al. (2015)
c.281G>A p.Gly94Glu missense_variant Unknown - - 30132828 Mattison KA , et al. (2018)
c.471+20A>C - intron_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.*111C>G - missense_variant De novo - Simplex 29315614 Johannesen KM , et al. (2018)
c.*265G>A - missense_variant De novo - Simplex 29315614 Johannesen KM , et al. (2018)
c.913G>A p.Ala305Thr missense_variant Familial Maternal Simplex 37700749 et al. ()
c.959C>T p.Ser320Phe missense_variant Familial Maternal Simplex 37700749 et al. ()
c.213dup p.Tyr72LeufsTer135 frameshift_variant De novo - Simplex 37700749 et al. ()
c.179A>G p.Tyr60Cys missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1352A>G p.Asp451Gly missense_variant De novo - - 28554332 Bowling KM , et al. (2017)
c.703T>C p.Trp235Arg missense_variant Unknown - - 30132828 Mattison KA , et al. (2018)
c.317A>G p.Gln106Arg missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.761T>C p.Leu254Pro missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.130C>T p.Arg44Trp missense_variant De novo - Simplex 34006619 Kahen A et al. (2021)
c.578G>A p.Trp193Ter stop_gained De novo - Simplex 25865495 Carvill GL , et al. (2015)
c.1078G>A p.Gly360Ser missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.1024G>A p.Val342Met missense_variant De novo - - 27479843 Lelieveld SH et al. (2016)
c.1334A>G p.Tyr445Cys missense_variant Unknown - - 30132828 Mattison KA , et al. (2018)
c.1648G>A p.Gly550Arg missense_variant Unknown - - 30132828 Mattison KA , et al. (2018)
c.223G>A p.Gly75Arg missense_variant De novo - - 29315614 Johannesen KM , et al. (2018)
c.1349_1350del p.Phe450Ter frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.1081C>A p.Pro361Thr missense_variant De novo - Simplex 32398021 Wang J et al. (2020)
c.302A>G p.Glu101Gly missense_variant De novo - Simplex 34006619 Kahen A et al. (2021)
c.331G>A p.Gly111Arg missense_variant De novo - Simplex 34006619 Kahen A et al. (2021)
c.752T>C p.Leu251Pro missense_variant De novo - Simplex 34006619 Kahen A et al. (2021)
c.863C>T p.Ala288Val missense_variant De novo - Simplex 34006619 Kahen A et al. (2021)
c.884C>T p.Ser295Leu missense_variant De novo - Simplex 34006619 Kahen A et al. (2021)
c.889G>A p.Gly297Arg missense_variant De novo - Simplex 34006619 Kahen A et al. (2021)
c.919G>A p.Gly307Arg missense_variant De novo - Simplex 34006619 Kahen A et al. (2021)
c.980A>G p.Asn327Ser missense_variant De novo - Simplex 34006619 Kahen A et al. (2021)
c.991A>G p.Ser331Gly missense_variant De novo - Simplex 34006619 Kahen A et al. (2021)
c.149G>T p.Arg50Leu missense_variant De novo - Unknown 33619735 Brunet T et al. (2021)
c.154G>T p.Asp52Tyr missense_variant De novo - Simplex 36973392 Miyake N et al. (2023)
c.723C>A p.Tyr241Ter stop_gained Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.583C>T p.Arg195Cys missense_variant Familial Paternal - 33004838 Wang T et al. (2020)
c.1015T>C p.Phe339Leu missense_variant De novo - Simplex 27525107 Yuen RK et al. (2016)
c.1024G>A p.Val342Met missense_variant De novo - Simplex 34006619 Kahen A et al. (2021)
c.1084G>A p.Gly362Arg missense_variant De novo - Simplex 34006619 Kahen A et al. (2021)
c.850-2A>G - splice_site_variant De novo - Unknown 29315614 Johannesen KM , et al. (2018)
c.863C>T p.Ala288Val missense_variant Familial Maternal - 34006619 Kahen A et al. (2021)
c.1648G>A p.Gly550Arg missense_variant De novo - Simplex 25961944 Krumm N , et al. (2015)
c.1084G>A p.Gly362Arg missense_variant Unknown - Simplex 37457006 Caputo D et al. (2023)
c.1648G>A p.Gly550Arg missense_variant De novo - Simplex 37457006 Caputo D et al. (2023)
c.1702C>T p.Gln568Ter stop_gained Unknown - Multiplex 37502687 Kassabian B et al. (2023)
c.987C>A p.Cys329Ter stop_gained De novo - Simplex 29315614 Johannesen KM , et al. (2018)
c.1222del p.Leu408TrpfsTer26 frameshift_variant Unknown - - 34006619 Kahen A et al. (2021)
c.1255del p.Arg419AlafsTer15 frameshift_variant Unknown - - 34006619 Kahen A et al. (2021)
c.896G>T p.Gly299Val missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.752T>C p.Ile251Thr missense_variant De novo - Simplex 31406558 Munnich A , et al. (2019)
c.739C>G p.Pro247Ala missense_variant De novo - Simplex 32913952 Hinokuma N et al. (2020)
c.919G>A p.Gly307Arg missense_variant De novo - Simplex 36674476 Piniella D et al. (2023)
c.131G>A p.Arg44Gln missense_variant De novo - Simplex 25865495 Carvill GL , et al. (2015)
c.137C>T p.Thr46Met missense_variant De novo - Simplex 28472652 Willsey AJ , et al. (2017)
c.1600C>T p.Gln534Ter stop_gained De novo - Simplex 29315614 Johannesen KM , et al. (2018)
c.1377C>A p.Ser459Arg missense_variant De novo - Simplex 32277047 Chevarin M et al. (2020)
c.863C>T p.Ala288Val missense_variant De novo - Simplex 22495306 Sanders SJ , et al. (2012)
c.640_658del p.Leu214SerfsTer32 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.1163T>G p.Met388Arg missense_variant De novo - Simplex 36582431 Verhoeven W et al. (2022)
c.493G>T p.Asp165Tyr missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.514C>T p.Arg172Cys missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.340G>A p.Gly114Arg missense_variant Unknown - Multiplex 37502687 Kassabian B et al. (2023)
c.160C>T p.Leu54Phe missense_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.167C>T p.Ser56Phe missense_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.1000G>C p.Ala334Pro missense_variant Familial Maternal - 25865495 Carvill GL , et al. (2015)
c.1531G>A p.Val511Met missense_variant De novo - Simplex 37662110 Johannesen KM et al. (2023)
c.419A>G p.Tyr140Cys missense_variant De novo - Simplex 29315614 Johannesen KM , et al. (2018)
c.434C>T p.Ser145Phe missense_variant De novo - Simplex 29315614 Johannesen KM , et al. (2018)
c.695G>T p.Gly232Val missense_variant De novo - Simplex 29315614 Johannesen KM , et al. (2018)
c.809T>C p.Phe270Ser missense_variant De novo - Simplex 29315614 Johannesen KM , et al. (2018)
c.863C>T p.Ala288Val missense_variant De novo - Simplex 29315614 Johannesen KM , et al. (2018)
c.593A>C p.His198Pro missense_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.863C>T p.Ala288Val missense_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.919G>A p.Gly307Arg missense_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.1070C>T p.Ala357Val missense_variant De novo - - 35322241 Brea-Fernández AJ et al. (2022)
c.1793A>G p.Tyr598Cys missense_variant Familial Paternal - 25363760 De Rubeis S , et al. (2014)
c.1024G>A p.Val342Met missense_variant De novo - Simplex 29315614 Johannesen KM , et al. (2018)
c.1070C>T p.Ala357Val missense_variant De novo - Simplex 29315614 Johannesen KM , et al. (2018)
c.1155C>G p.Phe385Leu missense_variant De novo - Simplex 29315614 Johannesen KM , et al. (2018)
c.1000G>A p.Ala334Thr missense_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.1743G>C p.Glu581Asp missense_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.160C>T p.Leu54Phe missense_variant De novo - Simplex 33431980 Alonso-Gonzalez A et al. (2021)
c.700G>A p.Gly234Ser missense_variant Unknown Not paternal Simplex 31176687 Cai K , et al. (2019)
c.1702C>T p.Gln568Ter stop_gained Familial Paternal Multiplex 37502687 Kassabian B et al. (2023)
c.881_883del p.Ser294del inframe_deletion De novo - Simplex 29315614 Johannesen KM , et al. (2018)
c.863C>T p.Ala288Val missense_variant Unknown - Not simplex 29315614 Johannesen KM , et al. (2018)
c.286C>G p.Pro96Ala missense_variant Familial Paternal Simplex 37502687 Kassabian B et al. (2023)
c.1024G>A p.Val342Met missense_variant De novo - Not simplex 29315614 Johannesen KM , et al. (2018)
c.863C>T p.Ala288Val missense_variant Familial Maternal Simplex 25865495 Carvill GL , et al. (2015)
c.1070C>T p.Ala357Val missense_variant Familial Paternal Simplex 37502687 Kassabian B et al. (2023)
c.889G>A p.Gly297Arg missense_variant Familial Paternal Multiplex 37502687 Kassabian B et al. (2023)
c.1084G>C p.Gly362Arg missense_variant Familial Maternal Multiplex 37502687 Kassabian B et al. (2023)
c.1337del p.Val446AlafsTer13 frameshift_variant De novo - Simplex 37662110 Johannesen KM et al. (2023)
c.638dup p.Leu214ThrfsTer68 frameshift_variant De novo - Simplex 29315614 Johannesen KM , et al. (2018)
c.1349_1351del p.Phe450_Asp451delinsTyr inframe_deletion De novo - - 30132828 Mattison KA , et al. (2018)
c.1084G>A p.Gly362Arg missense_variant Familial Maternal Simplex 29315614 Johannesen KM , et al. (2018)
c.695G>T p.Gly232Val missense_variant Familial Maternal Multiplex 29315614 Johannesen KM , et al. (2018)
c.1369_1370del p.Gly457HisfsTer10 frameshift_variant De novo - Simplex 25865495 Carvill GL , et al. (2015)
c.194G>A p.Gly65Asp missense_variant Unknown Not maternal Multiplex 37662110 Johannesen KM et al. (2023)
c.723C>A p.Tyr241Ter stop_gained De novo - Multiplex (suspected twins) 28191889 Stessman HA , et al. (2017)
c.801del p.Ile268SerfsTer36 frameshift_variant Familial Paternal Simplex 37502687 Kassabian B et al. (2023)
c.283G>T p.Val95Phe missense_variant Familial Maternal Multi-generational 37502687 Kassabian B et al. (2023)
c.1679dup p.Ser562LeufsTer24 frameshift_variant Familial Maternal Unknown 37662110 Johannesen KM et al. (2023)
c.373G>A p.Val125Met missense_variant De novo (germline mosaicism) - Multiplex 33961861 Poliquin S et al. (2021)
c.1328G>A p.Gly443Asp missense_variant De novo (germline mosaicism) - Multiplex 37502687 Kassabian B et al. (2023)
c.1084G>A p.Gly362Arg missense_variant Familial Maternal Extended multiplex 29315614 Johannesen KM , et al. (2018)
c.1024G>A p.Val342Met missense_variant Familial Paternal Multi-generational 29315614 Johannesen KM , et al. (2018)
Common Variants   (3)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.-216+5824G>T;c.-155+5824G>T - intron_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.-215-4116T>C;c.-154-4116T>C - 2_KB_upstream_variant - - - 28442423 Yuan FF , et al. (2017)
SFARI Gene score
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 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."

4/1/2021
1
icon
1

Score remained at 1

Description

A de novo missense variant in the SLC6A1 gene (p.Ala288Val) 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). This missense variant was predicted to be damaging, and an amino acid substitution at the same residue (p.Ala288Cys) had previously been shown to reduce GABA transport activity to 5%-7% of wild-type activity (PMID 18381286). 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. Phenotypic evaluation of 34 individuals (30 novel, 4 previously published) with SLC6A1 mutations in Johannesen et al., 2018 demonstrated that impaired cognitive development (intellectual disability or learning disability) and epilepsy were the most common phenotypes; in addition, behavioral problems were frequently observed in individuals in this study, with eight patients presenting with ASD or autistic features.

Reports Added
[Genetic mosaicism, intrafamilial phenotypic heterogeneity, and molecular defects of a novel missense SLC6A1 mutation associated with epilepsy and ADHD2021] [Neurodevelopmental phenotypes associated with pathogenic variants in SLC6A12021] [Common molecular mechanisms of SLC6A1 variant-mediated neurodevelopmental disorders in astrocytes and neurons2021]
1/1/2021
1
icon
1

Score remained at 1

Description

A de novo missense variant in the SLC6A1 gene (p.Ala288Val) 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). This missense variant was predicted to be damaging, and an amino acid substitution at the same residue (p.Ala288Cys) had previously been shown to reduce GABA transport activity to 5%-7% of wild-type activity (PMID 18381286). 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. Phenotypic evaluation of 34 individuals (30 novel, 4 previously published) with SLC6A1 mutations in Johannesen et al., 2018 demonstrated that impaired cognitive development (intellectual disability or learning disability) and epilepsy were the most common phenotypes; in addition, behavioral problems were frequently observed in individuals in this study, with eight patients presenting with ASD or autistic features.

Reports Added
[Exploring the biological role of postzygotic and germinal de novo mutations in ASD2021] [De novo variants in neurodevelopmental disorders-experiences from a tertiary care center2021]
10/1/2020
1
icon
1

Score remained at 1

Description

A de novo missense variant in the SLC6A1 gene (p.Ala288Val) 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). This missense variant was predicted to be damaging, and an amino acid substitution at the same residue (p.Ala288Cys) had previously been shown to reduce GABA transport activity to 5%-7% of wild-type activity (PMID 18381286). 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. Phenotypic evaluation of 34 individuals (30 novel, 4 previously published) with SLC6A1 mutations in Johannesen et al., 2018 demonstrated that impaired cognitive development (intellectual disability or learning disability) and epilepsy were the most common phenotypes; in addition, behavioral problems were frequently observed in individuals in this study, with eight patients presenting with ASD or autistic features.

Reports Added
[Clinical and genetic characteristics of patients with Doose syndrome2020] [Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders2020]
7/1/2020
1
icon
1

Score remained at 1

Description

A de novo missense variant in the SLC6A1 gene (p.Ala288Val) 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). This missense variant was predicted to be damaging, and an amino acid substitution at the same residue (p.Ala288Cys) had previously been shown to reduce GABA transport activity to 5%-7% of wild-type activity (PMID 18381286). 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. Phenotypic evaluation of 34 individuals (30 novel, 4 previously published) with SLC6A1 mutations in Johannesen et al., 2018 demonstrated that impaired cognitive development (intellectual disability or learning disability) and epilepsy were the most common phenotypes; in addition, behavioral problems were frequently observed in individuals in this study, with eight patients presenting with ASD or autistic features.

Reports Added
[SLC6A1 G443D associated with developmental delay and epilepsy2020]
4/1/2020
1
icon
1

Score remained at 1

Description

A de novo missense variant in the SLC6A1 gene (p.Ala288Val) 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). This missense variant was predicted to be damaging, and an amino acid substitution at the same residue (p.Ala288Cys) had previously been shown to reduce GABA transport activity to 5%-7% of wild-type activity (PMID 18381286). 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. Phenotypic evaluation of 34 individuals (30 novel, 4 previously published) with SLC6A1 mutations in Johannesen et al., 2018 demonstrated that impaired cognitive development (intellectual disability or learning disability) and epilepsy were the most common phenotypes; in addition, behavioral problems were frequently observed in individuals in this study, with eight patients presenting with ASD or autistic features.

Reports Added
[Excess of de novo variants in genes involved in chromatin remodelling in patients with marfanoid habitus and intellectual disability2020] [Endoplasmic reticulum retention and degradation of a mutation in SLC6A1 associated with epilepsy and autism2020] [Phenotypic and genetic spectrum of epilepsy with myoclonic atonic seizures2020]
1/1/2020
1
icon
1

Score remained at 1

Description

A de novo missense variant in the SLC6A1 gene (p.Ala288Val) 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). This missense variant was predicted to be damaging, and an amino acid substitution at the same residue (p.Ala288Cys) had previously been shown to reduce GABA transport activity to 5%-7% of wild-type activity (PMID 18381286). 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. Phenotypic evaluation of 34 individuals (30 novel, 4 previously published) with SLC6A1 mutations in Johannesen et al., 2018 demonstrated that impaired cognitive development (intellectual disability or learning disability) and epilepsy were the most common phenotypes; in addition, behavioral problems were frequently observed in individuals in this study, with eight patients presenting with ASD or autistic features.

Reports Added
[Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism2020]
10/1/2019
2S
icon
1

Decreased from 2S to 1

New Scoring Scheme
Description

A de novo missense variant in the SLC6A1 gene (p.Ala288Val) 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). This missense variant was predicted to be damaging, and an amino acid substitution at the same residue (p.Ala288Cys) had previously been shown to reduce GABA transport activity to 5%-7% of wild-type activity (PMID 18381286). 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. Phenotypic evaluation of 34 individuals (30 novel, 4 previously published) with SLC6A1 mutations in Johannesen et al., 2018 demonstrated that impaired cognitive development (intellectual disability or learning disability) and epilepsy were the most common phenotypes; in addition, behavioral problems were frequently observed in individuals in this study, with eight patients presenting with ASD or autistic features.

Reports Added
[New Scoring Scheme]
7/1/2019
2S
icon
2S

Decreased from 2S to 2S

Description

A de novo missense variant in the SLC6A1 gene (p.Ala288Val) 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). This missense variant was predicted to be damaging, and an amino acid substitution at the same residue (p.Ala288Cys) had previously been shown to reduce GABA transport activity to 5%-7% of wild-type activity (PMID 18381286). 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. Phenotypic evaluation of 34 individuals (30 novel, 4 previously published) with SLC6A1 mutations in Johannesen et al., 2018 demonstrated that impaired cognitive development (intellectual disability or learning disability) and epilepsy were the most common phenotypes; in addition, behavioral problems were frequently observed in individuals in this study, with eight patients presenting with ASD or autistic features.

Reports Added
[The Clinical and Genetic Features of Co-occurring Epilepsy and Autism Spectrum Disorder in Chinese Children.2019] [A missense mutation in SLC6A1 associated with Lennox-Gastaut syndrome impairs GABA transporter 1 protein trafficking and function.2019] [Clinical utility of multigene panel testing in adults with epilepsy and intellectual disability.2019] [Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder.2019]
4/1/2019
2S
icon
2S

Decreased from 2S to 2S

Description

A de novo missense variant in the SLC6A1 gene (p.Ala288Val) 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). This missense variant was predicted to be damaging, and an amino acid substitution at the same residue (p.Ala288Cys) had previously been shown to reduce GABA transport activity to 5%-7% of wild-type activity (PMID 18381286). 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. Phenotypic evaluation of 34 individuals (30 novel, 4 previously published) with SLC6A1 mutations in Johannesen et al., 2018 demonstrated that impaired cognitive development (intellectual disability or learning disability) and epilepsy were the most common phenotypes; in addition, behavioral problems were frequently observed in individuals in this study, with eight patients presenting with ASD or autistic features.

Reports Added
[Neurological Diseases With Autism Spectrum Disorder: Role of ASD Risk Genes.2019]
10/1/2018
2S
icon
2S

Decreased from 2S to 2S

Description

A de novo missense variant in the SLC6A1 gene (p.Ala288Val) 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). This missense variant was predicted to be damaging, and an amino acid substitution at the same residue (p.Ala288Cys) had previously been shown to reduce GABA transport activity to 5%-7% of wild-type activity (PMID 18381286). 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. Phenotypic evaluation of 34 individuals (30 novel, 4 previously published) with SLC6A1 mutations in Johannesen et al., 2018 demonstrated that impaired cognitive development (intellectual disability or learning disability) and epilepsy were the most common phenotypes; in addition, behavioral problems were frequently observed in individuals in this study, with eight patients presenting with ASD or autistic features.

Reports Added
[SLC6A1 variants identified in epilepsy patients reduce -aminobutyric acid transport.2018]
7/1/2018
2
icon
2S

Decreased from 2 to 2S

Description

A de novo missense variant in the SLC6A1 gene (p.Ala288Val) 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). This missense variant was predicted to be damaging, and an amino acid substitution at the same residue (p.Ala288Cys) had previously been shown to reduce GABA transport activity to 5%-7% of wild-type activity (PMID 18381286). 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. Phenotypic evaluation of 34 individuals (30 novel, 4 previously published) with SLC6A1 mutations in Johannesen et al., 2018 demonstrated that impaired cognitive development (intellectual disability or learning disability) and epilepsy were the most common phenotypes; in addition, behavioral problems were frequently observed in individuals in this study, with eight patients presenting with ASD or autistic features.

Reports Added
[Language Regression in an Atypical SLC6A1 Mutation.2018]
7/1/2017
2
icon
2

Decreased from 2 to 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.

Reports Added
[Using medical exome sequencing to identify the causes of neurodevelopmental disorders: experience of two clinical units and 216 patients.2017]
4/1/2017
2
icon
2

Decreased from 2 to 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.

Reports Added
[De novo mutations revealed by whole-exome sequencing are strongly associated with autism.2012] [Mutations in the GABA Transporter SLC6A1 Cause Epilepsy with Myoclonic-Atonic Seizures.2015] [Excess of rare, inherited truncating mutations in autism.2015] [Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci.2015] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016] [Genome-wide characteristics of de novo mutations in autism2016] [Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.2017] [Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder2017] [SLC6A1 gene involvement in susceptibility to attention-deficit/hyperactivity disorder: A case-control study and gene-environment interaction.2017] [De Novo Coding Variants Are Strongly Associated with Tourette Disorder.2017] [Genomic diagnosis for children with intellectual disability and/or developmental delay.2017]
1/1/2017
2
icon
2

Decreased from 2 to 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.

Reports Added
[Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.2017]
7/1/2016
2
icon
2

Decreased from 2 to 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).

Reports Added
[Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016] [Genome-wide characteristics of de novo mutations in autism2016]
1/1/2016
2
icon
2

Decreased from 2 to 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).

Reports Added
[De novo mutations revealed by whole-exome sequencing are strongly associated with autism.2012] [Mutations in the GABA Transporter SLC6A1 Cause Epilepsy with Myoclonic-Atonic Seizures.2015] [Excess of rare, inherited truncating mutations in autism.2015] [Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci.2015] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Low load for disruptive mutations in autism genes and their biased transmission.2015]
10/1/2015
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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).

Krishnan Probability Score

Score 0.6100404632439

Ranking 238/25841 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 0.99930187916582

Ranking 1000/18225 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
Iossifov Probability Score

Score 0.843

Ranking 201/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Original Source
Sanders TADA Score

Score 0.029094456788286

Ranking 38/18665 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
Zhang D Score

Score 0.034682481977119

Ranking 7636/20870 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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