Human Gene Module / Chromosome 8 / EXT1

EXT1Exostosin 1

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
5 / 7
Rare Variants / Common Variants
7 / 1
Aliases
EXT1, EXT,  LGCR,  LGS,  TRPS2,  TTV
Associated Syndromes
-
Chromosome Band
8q24.11
Associated Disorders
-
Relevance to Autism

Deletion mutations in the EXT1 gene were detected in two boys from separate families presenting with hereditary multiple exostoses and autism associated with mental retardation (Li et al., 2002). Inactivation of the EXT1 gene in mice resulted in impairments in social interaction, expression of stereotyped, repetitive behavior, and impairments in ultrasonic vocalization, as well as some associated features (Irie et al., 2012).

Molecular Function

This gene encodes an endoplasmic reticulum-resident type II transmembrane glycosyltransferase involved in the chain elongation step of heparan sulfate biosynthesis. Appears to be a tumor suppressor. Mutations in this gene are responsible for multiple hereditary exostoses (an autosomal dominant disorder characterized by multiple projections of bone capped by cartilage), trichorhinophalangeal syndrome type II, and possibly chondrosarcoma.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to EXT1 (7 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Association of autism in two patients with hereditary multiple exostoses caused by novel deletion mutations of EXT1 Li H , et al. (2002) Yes MR
2 Recent Recommendation Autism-like socio-communicative deficits and stereotypies in mice lacking heparan sulfate Irie F , et al. (2012) No -
3 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
4 Positive Association Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium (2017) Yes -
5 Support Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder Krupp DR , et al. (2017) Yes -
6 Support - Zhou X et al. (2022) Yes -
7 Highly Cited The putative tumor suppressors EXT1 and EXT2 are glycosyltransferases required for the biosynthesis of heparan sulfate Lind T , et al. (1998) No -
Rare Variants   (7)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.500C>T p.Ser167Leu missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.1772G>T p.Gly591Val missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1503C>T p.Leu501%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1600G>A p.Val534Met missense_variant De novo - Simplex 28867142 Krupp DR , et al. (2017)
c.1641_1642insCA p.Ser548GlnfsTer74 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.2094del p.Phe698LeufsTer8 frameshift_variant Familial Paternal Simplex 12032595 Li H , et al. (2002)
c.1742del p.Val581GlyfsTer40 frameshift_variant Familial Paternal Simplex 12032595 Li H , et al. (2002)
Common Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.962+27405T>A - intron_variant - - - 28540026 Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium (2017)
SFARI Gene score
2

Strong Candidate

Deletion mutations in the EXT1 gene were detected in two boys from separate families presenting with hereditary multiple exostoses and autism associated with mental retardation (PMID 12032595). Inactivation of the EXT1 gene in mice resulted in impairments in social interaction, expression of stereotyped, repetitive behavior, and impairments in ultrasonic vocalization, as well as some associated features (Irie et al., 2012).

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

Deletion mutations in the EXT1 gene were detected in two boys from separate families presenting with hereditary multiple exostoses and autism associated with mental retardation (PMID 12032595). Inactivation of the EXT1 gene in mice resulted in impairments in social interaction, expression of stereotyped, repetitive behavior, and impairments in ultrasonic vocalization, as well as some associated features (Irie et al., 2012).

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Deletion mutations in the EXT1 gene were detected in two boys from separate families presenting with hereditary multiple exostoses and autism associated with mental retardation (PMID 12032595). Inactivation of the EXT1 gene in mice resulted in impairments in social interaction, expression of stereotyped, repetitive behavior, and impairments in ultrasonic vocalization, as well as some associated features (Irie et al., 2012).

Reports Added
[New Scoring Scheme]
10/1/2017
4
icon
4

Decreased from 4 to 4

Description

Deletion mutations in the EXT1 gene were detected in two boys from separate families presenting with hereditary multiple exostoses and autism associated with mental retardation (PMID 12032595). Inactivation of the EXT1 gene in mice resulted in impairments in social interaction, expression of stereotyped, repetitive behavior, and impairments in ultrasonic vocalization, as well as some associated features (Irie et al., 2012).

Reports Added
[Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder.2017]
4/1/2017
4
icon
4

Decreased from 4 to 4

Description

Deletion mutations in the EXT1 gene were detected in two boys from separate families presenting with hereditary multiple exostoses and autism associated with mental retardation (PMID 12032595). Inactivation of the EXT1 gene in mice resulted in impairments in social interaction, expression of stereotyped, repetitive behavior, and impairments in ultrasonic vocalization, as well as some associated features (Irie et al., 2012).

Reports Added
[Association of autism in two patients with hereditary multiple exostoses caused by novel deletion mutations of EXT1.2002] [The putative tumor suppressors EXT1 and EXT2 are glycosyltransferases required for the biosynthesis of heparan sulfate.1998] [Autism-like socio-communicative deficits and stereotypies in mice lacking heparan sulfate.2012] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with ...2017]
1/1/2016
4
icon
4

Decreased from 4 to 4

Description

Deletion mutations in the EXT1 gene were detected in two boys from separate families presenting with hereditary multiple exostoses and autism associated with mental retardation (PMID 12032595). Inactivation of the EXT1 gene in mice resulted in impairments in social interaction, expression of stereotyped, repetitive behavior, and impairments in ultrasonic vocalization, as well as some associated features (Irie et al., 2012).

Reports Added
[Association of autism in two patients with hereditary multiple exostoses caused by novel deletion mutations of EXT1.2002] [The putative tumor suppressors EXT1 and EXT2 are glycosyltransferases required for the biosynthesis of heparan sulfate.1998] [Autism-like socio-communicative deficits and stereotypies in mice lacking heparan sulfate.2012] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014]
7/1/2014
No data
icon
4

Increased from No data to 4

Description

Deletion mutations in the EXT1 gene were detected in two boys from separate families presenting with hereditary multiple exostoses and autism associated with mental retardation (PMID 12032595). Inactivation of the EXT1 gene in mice resulted in impairments in social interaction, expression of stereotyped, repetitive behavior, and impairments in ultrasonic vocalization, as well as some associated features (Irie et al., 2012).

4/1/2014
No data
icon
4

Increased from No data to 4

Description

Deletion mutations in the EXT1 gene were detected in two boys from separate families presenting with hereditary multiple exostoses and autism associated with mental retardation (PMID 12032595). Inactivation of the EXT1 gene in mice resulted in impairments in social interaction, expression of stereotyped, repetitive behavior, and impairments in ultrasonic vocalization, as well as some associated features (Irie et al., 2012).

Krishnan Probability Score

Score 0.49393878140573

Ranking 3907/25841 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 0.99932048511126

Ranking 992/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.80478027456255

Ranking 2294/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Larsen Cumulative Evidence Score

Score 4

Ranking 307/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
Zhang D Score

Score 0.37912606714314

Ranking 1686/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
B3GNT1 UDP-GlcNAc:betaGal beta-1,3-N-acetylglucosaminyltransferase 1 Human Protein Binding 11041 O43505
C19ORF46 Nesprin-4 Human Protein Binding 163183 Q8N205-2
CNTF ciliary neurotrophic factor Human Protein Binding 1270 P26441
ERGIC3 ERGIC and golgi 3 Human Protein Binding 51614 A2TJK5
GAA Lysosomal alpha-glucosidase Human Protein Binding 2548 P10253
LRRC33 Negative regulator of reactive oxygen species Human Protein Binding 375387 Q86YC3
NAAA N-acylethanolamine acid amidase Human Protein Binding 27163 Q02083
PLAUR plasminogen activator, urokinase receptor Human Protein Binding 5329 Q03405
SCGB2A2 Mammaglobin-A Human Protein Binding 4250 Q13296-2
SLC39A5 Zinc transporter ZIP5 Human Protein Binding 283375 Q6ZMH5
Sotv CG8433 gene product from transcript CG8433-RA Fruit Fly Protein Binding 3772101 Q9Y169
TFR2 Transferrin receptor protein 2 Human Protein Binding E7ET36
TOR1AIP2 torsin A interacting protein 2 Human Protein Binding 163590 Q8NFQ8
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