Human Gene Module / Chromosome X / TSPYL2

TSPYL2TSPY like 2

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
2 / 6
Rare Variants / Common Variants
7 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
Xp11.22
Associated Disorders
-
Relevance to Autism

A hemizygous missense variant in the TSPYL2 gene was identified in two ASD-affected brothers from a Qatari ASD cohort (Al-Sarraj et al., 2024). De novo missense variants and a de novo in-frame deletion variant in this gene have previously been identified in male ASD probands from the SPARK cohort (Zhou et al., 2022). Tspyl2 loss-of-function mice have been shown to exhibit downregulation of N-methyl-D-aspartate receptor subunits 2A and 2B (GluN2A and GluN2B) in the hippocampus, impaired long-term potentiation at hippocampal Schaffer collateral-CA1 synapses, deficits in fear learning and memory, marginal increases in activity, significantly impaired prepulse inhibition, significantly increased sensitivity to the dopamine agonist amphetamine, and significantly smaller lateral ventricles (Tsang et al., 2014; Li et al., 2016). Tsang et al., 2014 also demonstrated by luciferase reporter assays and chromatin immunoprecipitation studies that TSPYL2 regulated the expression of Grin2a and Grin2b, the genes encoding GluN2A and GluN2B, and that TSPYL2 interacted with CREBBP, indicating that TSPYL2 may activate gene expression through this interaction. Moey et al., 2016 reported that Xp11.22 microduplications including IQSEC2, TSPYL2 and KDM5C were identified in four males presenting with intellectual disability, deficits in speech development, and behavior disturbances, including one individual with autism spectrum disorder; lymphoblastic cell lines from patients showed markedly elevated levels of TSPYL2 and KDM5C.

Molecular Function

This gene encodes a member of the testis-specific protein Y-encoded, TSPY-like/SET/nucleosome assembly protein-1 superfamily. The encoded protein is localized to the nucleolus where it functions in chromatin remodeling and as an inhibitor of cell-cycle progression. This protein is part of the CASK/TBR1/TSPYL2 transcriptional complex which modulates gene expression in response to neuronal synaptic activity, probably by facilitating nucleosome assembly (Wang et al., 2004).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
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SFARI Genomic Platforms
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Reports related to TSPYL2 (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support - Wang GS , et al. (2004) No -
2 Support - Ka Hing Tsang et al. (2014) No -
3 Support - Moey C , et al. (2015) No ASD, epilepsy/seizures
4 Support - Qi Li et al. (2016) No -
5 Support - Zhou X et al. (2022) Yes -
6 Primary - Yasser Al-Sarraj et al. (2024) Yes -
Rare Variants   (7)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_gain De novo - Simplex 26059843 Moey C , et al. (2015)
- - copy_number_gain Familial Maternal Simplex 26059843 Moey C , et al. (2015)
c.1048C>T p.Pro350Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1493G>A p.Ser498Asn missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1146_1148del p.Ile383del inframe_deletion De novo - - 35982159 Zhou X et al. (2022)
- - copy_number_gain Familial Maternal Extended multiplex 26059843 Moey C , et al. (2015)
c.1668G>C p.Gln556His missense_variant Familial Maternal Multiplex 38572415 Yasser Al-Sarraj et al. (2024)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

Score Delta: Score remained at 3

criteria met
See SFARI Gene'scoring criteria
3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

7/1/2024
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3

Increased from to 3

Krishnan Probability Score

Score 0.56801418160565

Ranking 1144/25841 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 0.87463582756265

Ranking 3432/18225 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 0.93440707200806

Ranking 12559/18665 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 0.26765482861317

Ranking 3221/20870 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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