Human Gene Module / Chromosome X / SLITRK2

SLITRK2SLIT and NTRK like family member 2

SFARI Gene Score
S
Syndromic Syndromic
Autism Reports / Total Reports
1 / 8
Rare Variants / Common Variants
16 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
Xq27.3
Associated Disorders
-
Relevance to Autism

El Chehadeh et al., 2022 reported eight individuals from seven unrelated families presenting a neurodevelopmental disorder characterized by developmental delay, intellectual disability, and behavioral/neuropsychiatric manifestations (including ASD in 4/8 individudals) and harboring rare potential disease-causing variants in SLITRK2; functional studies subsequently showed that some of these variants caused impaired surface trafficking in transfected HEK293T cells and impaired dendritic targeting in cultured hippocampal neurons, as well as an inability to rescue deficits in excitatory synapse development and transmission in Slitrk2-cKO hippocampal neurons. El Chehadeh et al., 2022 also demonstrated that Slitrk2 conditional knockout mice were found to exhibit impaired long-term memory and abnormal gait. Slitrk2 knockout mice had previously been shown to exhibit increased locomotor activity in novel environments, antidepressant-like behaviors, enhanced vestibular function, and increased plasticity at mossy fiber-CA3 synapses with reduced sensitivity to serotonin (Katayama et al., 2022). The protein encoded by the SLITRK2 gene has been shown to interact with the protein products of the ASD-associated genes SHANK3, DLG2, and DLG4, and these interactions are required for SLITRK2-mediated excitatory synapse development (Han et al., 2019; Loomis et al., 2020). A maternally-inherited SLITRK2 missense variant (p.Val89Met) that was originally identified as being transmitted to three sisters with schizophrenia in Piton et al., 2011 was experimentally shown in Kang et al., 2016 to compromise synapse formation activity in cultured hippocampal neurons.

Molecular Function

This gene encodes an integral membrane protein that contains two N-terminal leucine-rich repeats domains and contains C-terminal regions similar to neurotrophin receptors. The encoded protein may play a role in modulating neurite activity. It is involved in synaptogenesis and promotes excitatory synapse differentiation (Beaubien et al., 2016; Kang et al., 2016).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
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Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
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Reports related to SLITRK2 (8 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Systematic resequencing of X-chromosome synaptic genes in autism spectrum disorder and schizophrenia Piton A , et al. (2010) No -
2 Support - Beaubien F et al. (2016) No -
3 Support - Kang H et al. (2016) No -
4 Support - Han KA et al. (2019) No -
5 Support - Loomis C et al. (2020) No -
6 Support - Katayama KI et al. (2022) No -
7 Primary - El Chehadeh S et al. (2022) No ASD, ADHD, epilepsy/seizures
8 Support - Tayyaba Afsar et al. (2024) Yes -
Rare Variants   (16)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.26G>T p.Ser9Ile missense_variant Familial Maternal - 35840571 El Chehadeh S et al. (2022)
c.44G>A p.Gly15Glu missense_variant Familial Maternal - 35840571 El Chehadeh S et al. (2022)
c.931C>G p.Pro311Ala missense_variant Unknown - Simplex 35840571 El Chehadeh S et al. (2022)
c.1276C>T p.Arg426Cys missense_variant De novo - Simplex 35840571 El Chehadeh S et al. (2022)
c.1665G>C p.Glu555Asp missense_variant Unknown - Simplex 35840571 El Chehadeh S et al. (2022)
c.789T>A p.Cys263Ter stop_gained Familial Maternal Simplex 38283150 Tayyaba Afsar et al. (2024)
c.265G>A p.Val89Met missense_variant Familial Maternal Multiplex 20479760 Piton A , et al. (2010)
c.221T>C p.Leu74Ser missense_variant Familial Maternal Simplex 35840571 El Chehadeh S et al. (2022)
c.601G>A p.Val201Ile missense_variant Familial Maternal Simplex 35840571 El Chehadeh S et al. (2022)
c.628G>A p.Glu210Lys missense_variant Familial Maternal Simplex 35840571 El Chehadeh S et al. (2022)
c.934A>G p.Thr312Ala missense_variant Familial Maternal Simplex 35840571 El Chehadeh S et al. (2022)
c.1121C>G p.Pro374Arg missense_variant Familial Maternal Simplex 35840571 El Chehadeh S et al. (2022)
c.1451G>A p.Arg484Gln missense_variant Familial Maternal Simplex 35840571 El Chehadeh S et al. (2022)
c.1531G>A p.Val511Met missense_variant Familial Maternal Simplex 35840571 El Chehadeh S et al. (2022)
c.2374C>T p.Arg792Cys missense_variant Familial Maternal Simplex 35840571 El Chehadeh S et al. (2022)
c.1381G>T p.Glu461Ter stop_gained De novo (germline mosaicism) - Multiplex 35840571 El Chehadeh S et al. (2022)
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

Score Delta: Score remained at S

criteria met
See SFARI Gene'scoring criteria
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."

Krishnan Probability Score

Score 0.50008726776143

Ranking 2108/25841 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 0.24067471578033

Ranking 6797/18225 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 0.93803890295006

Ranking 13727/18665 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 0.24187183937358

Ranking 3593/20870 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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