Human Gene Module / Chromosome 13 / SLITRK5

SLITRK5SLIT and NTRK like family member 5

Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
5 / 9
Rare Variants / Common Variants
11 / 0
Aliases
SLITRK5, LRRC11,  bA364G4.2
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Functional
Chromosome Band
13q31.2
Associated Disorders
-
Relevance to Autism

A maternally-inherited nonsense variant in the SLITRK5 gene was identified in a male ASD proband, but not in this proband's ASD-affected brother, in Tammimies et al., 2015. Rare de novo missense variants that were predicted to be possibly damaging, as well as a de novo synonymous variant predicted to change an exonic splicing regulator, affect a DNase I hypersensitive site, and result in the gain of a miRNA target, were identified in the SLITRK5 gene in ASD probands from the Simons Simplex Collection (Iossifov et al., 2012; Iossifov et al., 2014; Takata et al., 2016). SLITRK5 variants that resulted in impaired synapse formation were identified in OCD probands in Song et al., 2017. Loss of Slitrk5 had previously been shown to result in OCD-like behaviors in mice, which manifests as excessive self-grooming and increased anxiety-like behaviors (Shmelkov et al., 2010).

Molecular Function

This gene enocdes a protein that suppresses neurite outgrowth; it is expressed predominantly in the cerebral cortex of the brain but also at low levels in the spinal cord and medulla.

Reports related to SLITRK5 (9 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Slitrk5 deficiency impairs corticostriatal circuitry and leads to obsessive-compulsive-like behaviors in mice. Shmelkov SV , et al. (2010) No -
2 Support De novo gene disruptions in children on the autistic spectrum. Iossifov I , et al. (2012) Yes -
3 Support The contribution of de novo coding mutations to autism spectrum disorder. Iossifov I , et al. (2014) Yes -
4 Support Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder. Tammimies K , et al. (2015) Yes -
5 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
6 Support Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease. Karaca E , et al. (2015) No Microcephaly
7 Recent Recommendation De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia. Takata A , et al. (2016) No -
8 Support Rare Synaptogenesis-Impairing Mutations in SLITRK5 Are Associated with Obsessive Compulsive Disorder. Song M , et al. (2017) No -
9 Support Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes. Guo H , et al. (2018) Yes -
Rare Variants   (11)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.297T>G p.Asn99Lys missense_variant Unknown - Unknown 28085938 Song M , et al. (2017)
c.175G>T p.Gly59Cys missense_variant De novo NA Simplex 30504930 Guo H , et al. (2018)
c.976C>T p.Pro326Ser missense_variant De novo NA Simplex 30504930 Guo H , et al. (2018)
c.1798G>A p.Glu600Lys missense_variant Unknown - Unknown 28085938 Song M , et al. (2017)
c.2552C>T p.Ala851Val missense_variant Unknown - Unknown 28085938 Song M , et al. (2017)
c.167A>G p.Glu56Gly missense_variant De novo NA Simplex 25363768 Iossifov I , et al. (2014)
c.224A>G p.Glu75Gly missense_variant De novo NA Simplex 25363768 Iossifov I , et al. (2014)
c.2164_2166del p.Gly722del inframe_deletion Unknown - Unknown 28085938 Song M , et al. (2017)
c.2625G>A p.Pro875%3D synonymous_variant De novo NA Simplex 22542183 Iossifov I , et al. (2012)
c.1695G>A p.Trp565Ter stop_gained Familial Maternal Multiplex 26325558 Tammimies K , et al. (2015)
c.2515G>C p.Glu839Gln missense_variant Familial Both parents Simplex 26539891 Karaca E , et al. (2015)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

A maternally-inherited nonsense variant in the SLITRK5 gene was identified in a male ASD proband, but not in this proband's ASD-affected brother, in Tammimies et al., 2015. Rare de novo missense variants that were predicted to be possibly damaging, as well as a de novo synonymous variant predicted to change an exonic splicing regulator, affect a DNase I hypersensitive site, and result in the gain of a miRNA target, were identified in the SLITRK5 gene in ASD probands from the Simons Simplex Collection (Iossifov et al., 2012; Iossifov et al., 2014; Takata et al., 2016). SLITRK5 variants that resulted in impaired synapse formation were identified in OCD probands in Song et al., 2017. Loss of Slitrk5 had previously been shown to result in OCD-like behaviors in mice, which manifests as excessive self-grooming and increased anxiety-like behaviors (Shmelkov et al., 2010).

Score Delta: Score remained at 3

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.

10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

A maternally-inherited nonsense variant in the SLITRK5 gene was identified in a male ASD proband, but not in this proband's ASD-affected brother, in Tammimies et al., 2015. Rare de novo missense variants that were predicted to be possibly damaging, as well as a de novo synonymous variant predicted to change an exonic splicing regulator, affect a DNase I hypersensitive site, and result in the gain of a miRNA target, were identified in the SLITRK5 gene in ASD probands from the Simons Simplex Collection (Iossifov et al., 2012; Iossifov et al., 2014; Takata et al., 2016). SLITRK5 variants that resulted in impaired synapse formation were identified in OCD probands in Song et al., 2017. Loss of Slitrk5 had previously been shown to result in OCD-like behaviors in mice, which manifests as excessive self-grooming and increased anxiety-like behaviors (Shmelkov et al., 2010).

Reports Added
[New Scoring Scheme]
10/1/2018
3
icon
3

Decreased from 3 to 3

Description

A maternally-inherited nonsense variant in the SLITRK5 gene was identified in a male ASD proband, but not in this proband's ASD-affected brother, in Tammimies et al., 2015. Rare de novo missense variants that were predicted to be possibly damaging, as well as a de novo synonymous variant predicted to change an exonic splicing regulator, affect a DNase I hypersensitive site, and result in the gain of a miRNA target, were identified in the SLITRK5 gene in ASD probands from the Simons Simplex Collection (Iossifov et al., 2012; Iossifov et al., 2014; Takata et al., 2016). SLITRK5 variants that resulted in impaired synapse formation were identified in OCD probands in Song et al., 2017. Loss of Slitrk5 had previously been shown to result in OCD-like behaviors in mice, which manifests as excessive self-grooming and increased anxiety-like behaviors (Shmelkov et al., 2010).

7/1/2018
icon
3

Increased from to 3

Description

A maternally-inherited nonsense variant in the SLITRK5 gene was identified in a male ASD proband, but not in this proband's ASD-affected brother, in Tammimies et al., 2015. Rare de novo missense variants that were predicted to be possibly damaging, as well as a de novo synonymous variant predicted to change an exonic splicing regulator, affect a DNase I hypersensitive site, and result in the gain of a miRNA target, were identified in the SLITRK5 gene in ASD probands from the Simons Simplex Collection (Iossifov et al., 2012; Iossifov et al., 2014; Takata et al., 2016). SLITRK5 variants that resulted in impaired synapse formation were identified in OCD probands in Song et al., 2017. Loss of Slitrk5 had previously been shown to result in OCD-like behaviors in mice, which manifests as excessive self-grooming and increased anxiety-like behaviors (Shmelkov et al., 2010).

Krishnan Probability Score

Score 0.60290656604839

Ranking 370/25841 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.
ExAC Score

Score 0.81208830838453

Ranking 3863/18225 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
Iossifov Probability Score

Score 0.907

Ranking 129/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Sanders TADA Score

Score 0.91725394219743

Ranking 8618/18665 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).
Zhang D Score

Score 0.068827008104702

Ranking 6776/20870 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.
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
SLC39A4 solute carrier family 39 (zinc transporter), member 4 Human Protein Binding 55630 Q6P5W5
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