Human Gene Module / Chromosome 15 / GABRB3

GABRB3gamma-aminobutyric acid (GABA) A receptor, beta 3

Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
19 / 34
Rare Variants / Common Variants
46 / 29
Aliases
GABRB3, MGC9051
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Genetic Association
Chromosome Band
15q12
Associated Disorders
ADHD, ASD, DD/NDD, ID
Relevance to Autism

Rare variants in the GABRB3 gene have been identified with autism (e.g. Cook et al., 1998) and genetic association has been found between GABRB3 and childhood absence epilepsy (CAE) (Urak et al., 2006). As well, a number of studies have found genetic association between the GABRB3 gene and autism (including one that enriched for savant skills). Populations studied include Caucasian, African-American, Hispanic, as well as AGRE, SARC and CLSA cohorts. However, other studies found no genetic association between the GABRB3 gene and autism in IMGSAC and other cohorts.

Molecular Function

The encoded protein is a subunit of GABA-A receptor. Neurotransmission is predominantly mediated by a gated chloride channel activity intrinsic to the receptor.

Reports related to GABRB3 (34 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Negative Association Serotonin transporter (5-HTT) and gamma-aminobutyric acid receptor subunit beta3 (GABRB3) gene polymorphisms are not associated with autism in the ... Maestrini E , et al. (1999) Yes -
2 Negative Association Absence of linkage and linkage disequilibrium to chromosome 15q11-q13 markers in 139 multiplex families with autism. Salmon B , et al. (1999) Yes -
3 Positive Association Association between a GABRB3 polymorphism and autism. Buxbaum JD , et al. (2002) Yes -
4 Positive Association Association analysis of chromosome 15 gabaa receptor subunit genes in autistic disorder. Menold MM , et al. (2002) Yes -
5 Positive Association Exploratory subsetting of autism families based on savant skills improves evidence of genetic linkage to 15q11-q13. Nurmi EL , et al. (2003) Yes -
6 Positive Association A linkage disequilibrium map of the 1-Mb 15q12 GABA(A) receptor subunit cluster and association to autism. McCauley JL , et al. (2004) Yes -
7 Positive Association An association analysis of microsatellite markers across the Prader-Willi/Angelman critical region on chromosome 15 (q11-13) and autism spectrum di... Curran S , et al. (2005) Yes -
8 Positive Association An analysis paradigm for investigating multi-locus effects in complex disease: examination of three GABA receptor subunit genes on 15q11-q13 as ris... Ashley-Koch AE , et al. (2006) Yes -
9 Recent Recommendation A GABRB3 promoter haplotype associated with childhood absence epilepsy impairs transcriptional activity. Urak L , et al. (2006) No -
10 Recent Recommendation Gabrb3 gene deficient mice exhibit impaired social and exploratory behaviors, deficits in non-selective attention and hypoplasia of cerebellar verm... DeLorey TM , et al. (2007) No -
11 Positive Association Maternal transmission of a rare GABRB3 signal peptide variant is associated with autism. Delahanty RJ , et al. (2009) Yes -
12 Recent Recommendation Somatosensory and sensorimotor consequences associated with the heterozygous disruption of the autism candidate gene, Gabrb3. DeLorey TM , et al. (2010) No -
13 Recent Recommendation Altered ultrasonic vocalization and impaired learning and memory in Angelman syndrome mouse model with a large maternal deletion from Ube3a to Gabrb3. Jiang YH , et al. (2010) No -
14 Support De novo gene disruptions in children on the autistic spectrum. Iossifov I , et al. (2012) Yes -
15 Recent Recommendation Variation in the autism candidate gene GABRB3 modulates tactile sensitivity in typically developing children. Tavassoli T , et al. (2012) No -
16 Support Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder. Girirajan S , et al. (2013) Yes -
17 Positive association De novo mutations in epileptic encephalopathies. Epi4K Consortium , et al. (2013) No IS, LGS, DD, ID, ASD, ADHD
18 Positive Association Genetic variation in GABRB3 is associated with Asperger syndrome and multiple endophenotypes relevant to autism. Warrier V , et al. (2013) Yes ALTs
19 Negative association Genetic analysis of GABRB3 as a candidate gene of autism spectrum disorders. Chen CH , et al. (2014) Yes -
20 Recent recommendation Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
21 Support Large-scale discovery of novel genetic causes of developmental disorders. Deciphering Developmental Disorders Study (2014) No -
22 Support Excess of rare, inherited truncating mutations in autism. Krumm N , et al. (2015) Yes -
23 Recent recommendation Incorporating Functional Information in Tests of Excess De Novo Mutational Load. Jiang Y , et al. (2015) No -
24 Recent recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
25 Support Gene Mutation Analysis in 253 Chinese Children with Unexplained Epilepsy and Intellectual/Developmental Disabilities. Zhang Y , et al. (2015) No -
26 Recent recommendation Compromising the phosphodependent regulation of the GABAAR 3 subunit reproduces the core phenotypes of autism spectrum disorders. Vien TN , et al. (2015) No -
27 Recent recommendation Systems genetics identifies a convergent gene network for cognition and neurodevelopmental disease. Johnson MR , et al. (2015) No -
28 Support Comprehensive molecular testing in patients with high functioning autism spectrum disorder. Alvarez-Mora MI , et al. (2016) Yes -
29 Support De Novo Mutations in SLC1A2 and CACNA1A Are Important Causes of Epileptic Encephalopathies. Epi4K Consortium. Electronic address: epi4k@columbia.edu and Epi4K Consortium (2016) No -
30 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Lelieveld SH , et al. (2016) No -
31 Support De novo genic mutations among a Chinese autism spectrum disorder cohort. Wang T , et al. (2016) Yes -
32 Support Diagnostic Targeted Resequencing in 349 Patients with Drug-Resistant Pediatric Epilepsies Identifies Causative Mutations in 30 Different Genes. Parrini E , et al. (2016) No Microcephaly
33 Highly Cited GABAA-receptor heterogeneity in the adult rat brain: differential regional and cellular distribution of seven major subunits. Fritschy JM and Mohler H (1995) No -
34 Primary Linkage-disequilibrium mapping of autistic disorder, with 15q11-13 markers. Cook EH Jr , et al. (1998) Yes -
Rare Variants   (46)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type Author, Year
c.31C>T p.Pro11Ser missense_variant Familial - - Delahanty RJ , et al. (2009)
c.489G>A p.Met163Ile missense_variant De novo - Simplex Iossifov I , et al. (2012)
- - copy_number_gain De novo - Simplex Girirajan S , et al. (2013)
c.328A>C p.Asn110His missense_variant De novo - - Epi4K Consortium , et al. (2013)
c.905A>G p.Tyr302Cys missense_variant De novo - - Epi4K Consortium , et al. (2013)
c.358G>A p.Asp120Asn missense_variant De novo - - Epi4K Consortium , et al. (2013)
c.539A>G p.Glu180Gly missense_variant De novo - - Epi4K Consortium , et al. (2013)
g.-1571T>C - 2KB_upstream_variant Unknown Not maternal Multiplex Chen CH , et al. (2014)
g.-1528T>C - 2KB_upstream_variant Familial Maternal Simplex Chen CH , et al. (2014)
c.-1533_-1526delCCTCATAinsTCCATTAGACAAAAGTCTG - indel, 2KB_upstream_variant Familial Paternal Simplex Chen CH , et al. (2014)
c.-1442G>A - 2KB_upstream_variant Unknown Not maternal Multi-generational Chen CH , et al. (2014)
c.-1437G>T - 2KB_upstream_variant Familial Paternal Simplex Chen CH , et al. (2014)
c.-1090A>G - 2KB_upstream_variant Familial Paternal Simplex Chen CH , et al. (2014)
c.-541T>C - 2KB_upstream_variant Familial Paternal Simplex Chen CH , et al. (2014)
c.-534C>T - 2KB_upstream_variant Familial Paternal Simplex Chen CH , et al. (2014)
c.-232G>T - 2KB_upstream_variant Familial Paternal Simplex Chen CH , et al. (2014)
c.-169G>T - 2KB_upstream_variant Familial Paternal Simplex Chen CH , et al. (2014)
c.-142G>T - 2KB_upstream_variant Familial Paternal Simplex Chen CH , et al. (2014)
c.-142G>T - 2KB_upstream_variant Familial Maternal Simplex Chen CH , et al. (2014)
c.-140A>T - 2KB_upstream_variant Familial Paternal Simplex Chen CH , et al. (2014)
c.-53G>T - 2KB_upstream_variant Familial Paternal Simplex Chen CH , et al. (2014)
c.557C>T p.Thr186Met missense_variant Familial Paternal Simplex Chen CH , et al. (2014)
c.942C>T p.(=) synonymous_variant Familial Paternal Simplex Chen CH , et al. (2014)
c.1006C>T p.Pro336Ser missense_variant Familial Maternal Simplex Chen CH , et al. (2014)
del(A) - frameshift_variant De novo - Simplex De Rubeis S , et al. (2014)
c.70G>T p.Glu24Ter stop_gained Unknown - Unknown De Rubeis S , et al. (2014)
ins(A) - frameshift_variant Unknown - Unknown De Rubeis S , et al. (2014)
c.662T>C p.Ile221Thr missense_variant De novo - Simplex Deciphering Developmental Disorders Study (2014)
c.232G>A p.Val78Ile missense_variant De novo - Simplex Krumm N , et al. (2015)
c.914C>T p.Ala305Val missense_variant De novo - Simplex Zhang Y , et al. (2015)
c.509T>G p.Leu170Arg missense_variant De novo - Simplex Zhang Y , et al. (2015)
c.31C>T p.Pro11Ser missense_variant Familial Paternal Multi-generational Alvarez-Mora MI , et al. (2016)
c.358G>A p.Asp120Asn missense_variant De novo - - Epi4K Consortium. Electronic address: epi4k@columbia.edu and Epi4K Consortium (2016)
c.470C>T p.Thr157Met missense_variant Familial - - Epi4K Consortium. Electronic address: epi4k@columbia.edu and Epi4K Consortium (2016)
c.545A>T p.Tyr182Phe missense_variant De novo - - Epi4K Consortium. Electronic address: epi4k@columbia.edu and Epi4K Consortium (2016)
c.745C>A p.Gln249Lys missense_variant De novo - - Epi4K Consortium. Electronic address: epi4k@columbia.edu and Epi4K Consortium (2016)
c.767T>A p.Leu256Gln missense_variant De novo - - Epi4K Consortium. Electronic address: epi4k@columbia.edu and Epi4K Consortium (2016)
c.878T>A p.Leu293His missense_variant Unknown - - Epi4K Consortium. Electronic address: epi4k@columbia.edu and Epi4K Consortium (2016)
c.913G>A p.Ala305Thr missense_variant De novo - - Epi4K Consortium. Electronic address: epi4k@columbia.edu and Epi4K Consortium (2016)
c.1412A>G p.Tyr471Cys missense_variant De novo - - Lelieveld SH , et al. (2016)
c.5G>A p.Trp2Ter stop_gained Familial Maternal - Wang T , et al. (2016)
c.5G>A p.Trp2Ter stop_gained Familial Paternal - Wang T , et al. (2016)
c.844C>T p.Arg282Cys missense_variant Familial - - Wang T , et al. (2016)
c.761C>T p.Ser254Phe missense_variant De novo - - Parrini E , et al. (2016)
c.372A>C p.Leu124Phe missense_variant De novo - - Parrini E , et al. (2016)
- - copy_number_gain Familial Maternal - Cook EH Jr , et al. (1998)
Common Variants   (29)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type Author, Year
N/A N/A intron_variant - - - Buxbaum JD , et al. (2002)
N/A N/A intron_variant - - - Buxbaum JD , et al. (2002)
- - microsatellite, intron_variant - - - Nurmi EL , et al. (2003)
- - intergenic_variant - - - McCauley JL , et al. (2004)
c.835+2039T>C;c.580+2039T>C;c.622+2039T>C A/G intron_variant - - - McCauley JL , et al. (2004)
c.241-728G>A - intron_variant - - - McCauley JL , et al. (2004)
c.241-1250G>A;c.-15-1250G>A;c.28-1250G>A T/C intron_variant - - - McCauley JL , et al. (2004)
c.241-62255G>A;c.-16+32825G>A;c.-111-41261G>A C/T intron_variant - - - McCauley JL , et al. (2004)
N/A N/A microsatellite - - - Curran S , et al. (2005)
c.241-55520T>G;c.-16+39560T>G;c.-111-34526T>G N/A intron_variant - - - Ashley-Koch AE , et al. (2006)
c.-1437T>G T/G 2KB_upstream_variant - - - Urak L , et al. (2006)
c.-1852G>A;c.-2203G>A;c.-1090G>A G/A 2KB_upstream_variant - - - Urak L , et al. (2006)
c.-1659T>C;c.-2010T>C;c.-897T>C T/C 2KB_upstream_variant - - - Urak L , et al. (2006)
c.-1493G>A;c.-1493G>C;c.-1493G>T;c.-1844G>A;c.-184 G/A 2KB_upstream_variant - - - Urak L , et al. (2006)
c.-1303C>T;c.-1654C>T;c.-541C>T T/C 2KB_upstream_variant - - - Urak L , et al. (2006)
- T/C 2KB_upstream_variant - - - Urak L , et al. (2006)
c.-931G>T;c.-1282G>T;c.-169G>T T/G 2KB_upstream_variant - - - Urak L , et al. (2006)
c.-828C>G;c.-1179C>G;c.-66C>G G/C 2KB_upstream_variant - - - Urak L , et al. (2006)
c.-732C>T;c.-1083C>T;c.31C>T p.Pro11Ser missense_variant, 2_KB_upstream_variant - - - Urak L , et al. (2006)
c.-688C>T;c.-1039C>T;c.75C>T p.(=) synonymous_variant, 2KB_upstream_variant - - - Urak L , et al. (2006)
C473A - 2KB_upstream_variant - - - Urak L , et al. (2006)
C662T - 2KB_upstream_variant - - - Urak L , et al. (2006)
c.240+12C>T;c.-112+12C>T - intron_variant - - - Urak L , et al. (2006)
c.240+39311C>T;c.-112+39311C>T A/G intron_variant - - - Warrier V , et al. (2013)
c.240+23093A>G;c.-112+23093A>G C/T intron_variant - - - Warrier V , et al. (2013)
c.240+29417T>G;c.-112+29417T>G C/A intron_variant - - - Warrier V , et al. (2013)
c.241-26347G>A;c.-15-26347G>A;c.-111-5353G>A T/C intron_variant - - - Warrier V , et al. (2013)
c.241-26705C>T;c.-15-26705C>T;c.-111-5711C>T A/G intron_variant - - - Warrier V , et al. (2013)
N/A N/A intron_variant - - - Cook EH Jr , et al. (1998)
SFARI Gene score
2

Strong Candidate

The gene lies within the 15q11-q13 duplication that, when maternally inherited, causes autism. There have been multiple gene-based association studies with mixed results; the gene has not been implicated in genome-wide association studies, nor have any of the gene-based associations been replicated. Knockout mice show social deficits and cerebellar vermis hypoplasia, and deficiency of MECP2 (a category S gene) causes decreased expression of GABRB3. A de novo LoF variant in the GABRB3 gene was identified in one ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760), while a de novo likely damaging missense variant in this gene has been observed in an ASD case from the Simons Simplex Collection (PMID 22542183). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified GABRB3 as a gene meeting high statistical significance with a 0.01 < FDR ?0.05, meaning that this gene had a ?95% chance of being a true autism gene (PMID 25363760).

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.

01-01-2017
2

Initial score established: 2

Description

The gene lies within the 15q11-q13 duplication that, when maternally inherited, causes autism. There have been multiple gene-based association studies with mixed results; the gene has not been implicated in genome-wide association studies, nor have any of the gene-based associations been replicated. Knockout mice show social deficits and cerebellar vermis hypoplasia, and deficiency of MECP2 (a category S gene) causes decreased expression of GABRB3. A de novo LoF variant in the GABRB3 gene was identified in one ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760), while a de novo likely damaging missense variant in this gene has been observed in an ASD case from the Simons Simplex Collection (PMID 22542183). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified GABRB3 as a gene meeting high statistical significance with a 0.01 < FDR ?0.05, meaning that this gene had a ?95% chance of being a true autism gene (PMID 25363760).

Reports Added
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CNVs associated with GABRB3(10 CNVs)
10p12.1 14 Deletion-Duplication 24  /  60
11p14.2 2 Deletion 4  /  6
15q11.1-q12 1 Duplication 2  /  1
15q13 1 Duplication 2  /  4
15q13.1 11 Deletion-Duplication 20  /  40
15q13.1-q13.2 9 Deletion-Duplication 16  /  20
16p12.1-q11.2 1 Deletion 1  /  1
1p36.11-p35.3 2 Deletion 4  /  2
22q12.1-q12.2 2 Deletion-Duplication 4  /  5
5p14.2-p14.1 1 Deletion 3  /  2
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
ACCN4 Acid-sensing ion channel 4 Human Protein Binding 55515 Q96FT7-4
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