Human Gene Module / Chromosome X / TSPAN7

TSPAN7tetraspanin 7

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
5 / 10
Rare Variants / Common Variants
10 / 0
Aliases
TSPAN7, A15,  MXS1,  CD231,  MRX58,  CCG-B7,  TM4SF2,  TALLA-1,  TM4SF2b,  DXS1692E
Associated Syndromes
-
Chromosome Band
Xp11.4
Associated Disorders
SCZ, ADHD, ASD
Relevance to Autism

Studies have found rare mutations in the TSPAN7 gene that are associated with autism (e.g. Piton et al., 2011), although one of these found that a TSPAN7 duplication did not disrupt gene expression and so likely was not the cause for the disease (they also found no other variants in their screening of other autistic patients) (Noor et al., 2009). In addition, studies have found rare variants in TSPAN7 that are associated with mental retardation.

Molecular Function

A cell surface glycoprotein with a role in the control of neurite outgrowth

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to TSPAN7 (10 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited A new gene involved in X-linked mental retardation identified by analysis of an X;2 balanced translocation Zemni R , et al. (2000) No -
2 Highly Cited A novel 2 bp deletion in the TM4SF2 gene is associated with MRX58 Abidi FE , et al. (2002) No -
3 Recent Recommendation Copy number variation analysis and sequencing of the X-linked mental retardation gene TSPAN7/TM4SF2 in patients with autism spectrum disorder Noor A , et al. (2009) Yes -
4 Primary Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia Piton A , et al. (2010) Yes SCZ
5 Support Interpretation of clinical relevance of X-chromosome copy number variations identified in a large cohort of individuals with cognitive disorders and/or congenital anomalies Willemsen MH , et al. (2012) No ASD, ADHD
6 Support Identification of risk genes for autism spectrum disorder through copy number variation analysis in Austrian families Egger G , et al. (2014) Yes -
7 Support X-linked intellectual disability related genes disrupted by balanced X-autosome translocations Moyss-Oliveira M , et al. (2015) No Microcephaly
8 Support - Pode-Shakked B et al. (2021) Yes -
9 Support - Pang S et al. (2022) Yes -
10 Support - Axel Schmidt et al. (2024) No Stereotypy
Rare Variants   (10)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - translocation - - - 10655063 Zemni R , et al. (2000)
- - copy_number_gain Unknown - - 24643514 Egger G , et al. (2014)
- - translocation Unknown - Unknown 26290131 Moyss-Oliveira M , et al. (2015)
- - copy_number_gain Familial Maternal - 22796527 Willemsen MH , et al. (2012)
c.274G>T p.Ala92Ser missense_variant Unknown - - 39039281 Axel Schmidt et al. (2024)
c.515C>A p.Pro172His missense_variant Familial Maternal - 20479760 Piton A , et al. (2010)
c.652G>T p.Gly218Ter stop_gained Familial Maternal Multiplex 10655063 Zemni R , et al. (2000)
c.515C>A p.Pro172His missense_variant Familial Maternal Multiplex 10655063 Zemni R , et al. (2000)
c.289del p.Leu97TrpfsTer8 frameshift_variant Familial Maternal - 34580403 Pode-Shakked B et al. (2021)
c.564del p.Leu189Ter frameshift_variant Familial Maternal Multi-generational 12070254 Abidi FE , et al. (2002)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

111 X-linked synaptic genes were sequenced in 140 ASD subjects (Piton et al., 2011). A P172H missense variant, which was associated earlier with mental retardation (MR) in two families, was identified. In the first MR study, the cosegregation of this variant with MR was not perfect, with one non-affected male carrying the variant. This variant was also identified by another team who screened patients with MR; it was absent in 77 ASD patients and 420 control chromosomes tested. The P172H variant (maternally inherited) was observed in one boy with ASD and MR in Piton et al. (2011). That study also utilized 190 controls and an additional 285 ASD subjects for replication by sequencing only the region containing this variant amino acid. In doing so, they found the same variant in another boy diagnosed with pervasive developmental disorder not otherwise specified without MR. This specific variant was neither present in 143 schizophrenia subjects nor in 190 ethnically matched control individuals. Taken together, these reports revealed that the P172H variant has not been found in 697 control X chromosomes (excluding relatives of the affected subjects). Marshall et al. (2008) identified a duplication overlapping this gene, but follow-up by Noor et al. (2009) found no coding mutations and no effect of the duplication on expression in lymphoblasts.

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

111 X-linked synaptic genes were sequenced in 140 ASD subjects (Piton et al., 2011). A P172H missense variant, which was associated earlier with mental retardation (MR) in two families, was identified. In the first MR study, the cosegregation of this variant with MR was not perfect, with one non-affected male carrying the variant. This variant was also identified by another team who screened patients with MR; it was absent in 77 ASD patients and 420 control chromosomes tested. The P172H variant (maternally inherited) was observed in one boy with ASD and MR in Piton et al. (2011). That study also utilized 190 controls and an additional 285 ASD subjects for replication by sequencing only the region containing this variant amino acid. In doing so, they found the same variant in another boy diagnosed with pervasive developmental disorder not otherwise specified without MR. This specific variant was neither present in 143 schizophrenia subjects nor in 190 ethnically matched control individuals. Taken together, these reports revealed that the P172H variant has not been found in 697 control X chromosomes (excluding relatives of the affected subjects). Marshall et al. (2008) identified a duplication overlapping this gene, but follow-up by Noor et al. (2009) found no coding mutations and no effect of the duplication on expression in lymphoblasts.

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

111 X-linked synaptic genes were sequenced in 140 ASD subjects (Piton et al., 2011). A P172H missense variant, which was associated earlier with mental retardation (MR) in two families, was identified. In the first MR study, the cosegregation of this variant with MR was not perfect, with one non-affected male carrying the variant. This variant was also identified by another team who screened patients with MR; it was absent in 77 ASD patients and 420 control chromosomes tested. The P172H variant (maternally inherited) was observed in one boy with ASD and MR in Piton et al. (2011). That study also utilized 190 controls and an additional 285 ASD subjects for replication by sequencing only the region containing this variant amino acid. In doing so, they found the same variant in another boy diagnosed with pervasive developmental disorder not otherwise specified without MR. This specific variant was neither present in 143 schizophrenia subjects nor in 190 ethnically matched control individuals. Taken together, these reports revealed that the P172H variant has not been found in 697 control X chromosomes (excluding relatives of the affected subjects). Marshall et al. (2008) identified a duplication overlapping this gene, but follow-up by Noor et al. (2009) found no coding mutations and no effect of the duplication on expression in lymphoblasts.

Reports Added
[New Scoring Scheme]
1/1/2016
4
icon
4

Decreased from 4 to 4

Description

111 X-linked synaptic genes were sequenced in 140 ASD subjects (Piton et al., 2011). A P172H missense variant, which was associated earlier with mental retardation (MR) in two families, was identified. In the first MR study, the cosegregation of this variant with MR was not perfect, with one non-affected male carrying the variant. This variant was also identified by another team who screened patients with MR; it was absent in 77 ASD patients and 420 control chromosomes tested. The P172H variant (maternally inherited) was observed in one boy with ASD and MR in Piton et al. (2011). That study also utilized 190 controls and an additional 285 ASD subjects for replication by sequencing only the region containing this variant amino acid. In doing so, they found the same variant in another boy diagnosed with pervasive developmental disorder not otherwise specified without MR. This specific variant was neither present in 143 schizophrenia subjects nor in 190 ethnically matched control individuals. Taken together, these reports revealed that the P172H variant has not been found in 697 control X chromosomes (excluding relatives of the affected subjects). Marshall et al. (2008) identified a duplication overlapping this gene, but follow-up by Noor et al. (2009) found no coding mutations and no effect of the duplication on expression in lymphoblasts.

Reports Added
[Copy number variation analysis and sequencing of the X-linked mental retardation gene TSPAN7/TM4SF2 in patients with autism spectrum disorder.2009] [Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia.2010] [Identification of risk genes for autism spectrum disorder through copy number variation analysis in Austrian families.2014] [Interpretation of clinical relevance of X-chromosome copy number variations identified in a large cohort of individuals with cognitive disorders an...2012] [A new gene involved in X-linked mental retardation identified by analysis of an X;2 balanced translocation.2000] [A novel 2 bp deletion in the TM4SF2 gene is associated with MRX58.2002] [X-linked intellectual disability related genes disrupted by balanced X-autosome translocations.2015]
7/1/2014
No data
icon
4

Increased from No data to 4

Description

111 X-linked synaptic genes were sequenced in 140 ASD subjects (Piton et al., 2011). A P172H missense variant, which was associated earlier with mental retardation (MR) in two families, was identified. In the first MR study, the cosegregation of this variant with MR was not perfect, with one non-affected male carrying the variant. This variant was also identified by another team who screened patients with MR; it was absent in 77 ASD patients and 420 control chromosomes tested. The P172H variant (maternally inherited) was observed in one boy with ASD and MR in Piton et al. (2011). That study also utilized 190 controls and an additional 285 ASD subjects for replication by sequencing only the region containing this variant amino acid. In doing so, they found the same variant in another boy diagnosed with pervasive developmental disorder not otherwise specified without MR. This specific variant was neither present in 143 schizophrenia subjects nor in 190 ethnically matched control individuals. Taken together, these reports revealed that the P172H variant has not been found in 697 control X chromosomes (excluding relatives of the affected subjects). Marshall et al. (2008) identified a duplication overlapping this gene, but follow-up by Noor et al. (2009) found no coding mutations and no effect of the duplication on expression in lymphoblasts.

4/1/2014
No data
icon
4

Increased from No data to 4

Description

111 X-linked synaptic genes were sequenced in 140 ASD subjects (Piton et al., 2011). A P172H missense variant, which was associated earlier with mental retardation (MR) in two families, was identified. In the first MR study, the cosegregation of this variant with MR was not perfect, with one non-affected male carrying the variant. This variant was also identified by another team who screened patients with MR; it was absent in 77 ASD patients and 420 control chromosomes tested. The P172H variant (maternally inherited) was observed in one boy with ASD and MR in Piton et al. (2011). That study also utilized 190 controls and an additional 285 ASD subjects for replication by sequencing only the region containing this variant amino acid. In doing so, they found the same variant in another boy diagnosed with pervasive developmental disorder not otherwise specified without MR. This specific variant was neither present in 143 schizophrenia subjects nor in 190 ethnically matched control individuals. Taken together, these reports revealed that the P172H variant has not been found in 697 control X chromosomes (excluding relatives of the affected subjects). Marshall et al. (2008) identified a duplication overlapping this gene, but follow-up by Noor et al. (2009) found no coding mutations and no effect of the duplication on expression in lymphoblasts.

Reports Added
[Identification of risk genes for autism spectrum disorder through copy number variation analysis in Austrian families.2014]
Krishnan Probability Score

Score 0.57115033059263

Ranking 817/25841 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 0.86995013142945

Ranking 3464/18225 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 0.9198791237991

Ranking 9081/18665 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 0

Ranking 461/461 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 -0.002626587739284

Ranking 8773/20870 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
nef Protein Nef HIV-1 Protein Binding 156110 P04601
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