Human Gene Module / Chromosome 15 / NTRK3

NTRK3neurotrophic tyrosine kinase, receptor, type 3

Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
4 / 13
Rare Variants / Common Variants
5 / 4
Aliases
NTRK3, TRKC,  gp145(trkC),  NTRK3
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic, Genetic Association
Chromosome Band
15q25.3
Associated Disorders
EPS, EP, ASD
Relevance to Autism

Genetic association has been found between the NTRK3 gene and both autism and Asperger syndrome (Chakrabarti et al., 2009). In addition, rare mutations NTRK3 have been found to be associated with panic disorder, and NTRK3 has been found to have genetic association with obsessive-compulsive disorder (Muios-Gimeno et al., 2009).

Molecular Function

A membrane-bound receptor that, upon neurotrophin binding, phosphorylates itself and members of the MAPK pathway

Reports related to NTRK3 (13 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited The neurotrophin receptor p75NTR as a positive modulator of myelination. Cosgaya JM , et al. (2002) No -
2 Highly Cited trkC, a new member of the trk family of tyrosine protein kinases, is a receptor for neurotrophin-3. Lamballe F , et al. (1991) No -
3 Recent Recommendation Gene expression patterns in brain cortex of three different animal models of depression. Urigen L , et al. (2008) No -
4 Recent Recommendation Neurotrophic factor-related gene polymorphisms and adult attention deficit hyperactivity disorder (ADHD) score in a high-risk male population. Conner AC , et al. (2008) No -
5 Recent Recommendation Allele variants in functional MicroRNA target sites of the neurotrophin-3 receptor gene (NTRK3) as susceptibility factors for anxiety disorders. Muios-Gimeno M , et al. (2009) No PD
6 Primary Genes related to sex steroids, neural growth, and social-emotional behavior are associated with autistic traits, empathy, and Asperger syndrome. Chakrabarti B , et al. (2009) Yes Asperger syndrome
7 Support Diagnostic exome sequencing in persons with severe intellectual disability. de Ligt J , et al. (2012) No Epilepsy, ASD
8 Support Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder. Girirajan S , et al. (2013) Yes -
9 Positive Association Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis. Cross-Disorder Group of the Psychiatric Genomics Consortium (2013) Yes -
10 Recent Recommendation Haplotype structure enables prioritization of common markers and candidate genes in autism spectrum disorder. Vardarajan BN , et al. (2013) No -
11 Support Genome-wide characteristics of de novo mutations in autism Yuen RK et al. (2016) Yes -
12 Highly Cited Disruption of the neurotrophin-3 receptor gene trkC eliminates la muscle afferents and results in abnormal movements. Klein R , et al. (1994) No -
13 Highly Cited Severe sensory and sympathetic deficits in mice lacking neurotrophin-3. Farias I , et al. (1994) No -
Rare Variants   (5)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
G>C - 3_prime_UTR_variant - - - 19370765 Muios-Gimeno M , et al. (2009)
T>C - 3_prime_UTR_variant - - - 19370765 Muios-Gimeno M , et al. (2009)
c.249-8635A>G - intron_variant De novo NA Simplex 27525107 Yuen RK et al. (2016)
- - copy_number_loss Familial Paternal Simplex 23375656 Girirajan S , et al. (2013)
c.2013C>T p.Ala671= synonymous_variant De novo NA - 23033978 de Ligt J , et al. (2012)
Common Variants   (4)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.1716+1044C>T;c.1692+1044C>T;c.1422+1044C>T;c.585+1044C>T G/A intron_variant - - - 19598235 Chakrabarti B , et al. (2009)
c.395+2937A>C;c.101+2937A>C T/G intron_variant - - - 23453885 Cross-Disorder Group of the Psychiatric Genomics Consortium (2013)
c.2134-1803C>T;c.2110-7110C>T;c.2134-7110C>T;c.2209-7110C>T;c.1003-7110C>T A/G intron_variant - - - 19598235 Chakrabarti B , et al. (2009)
c.*1296G>C;c.1586-37296G>C;c.1562-37296G>C;c.1292-37296G>C;c.455-37296G>C C/G intron_variant, 3_prime_UTR_variant - - - 19370765 Muios-Gimeno M , et al. (2009)
SFARI Gene score
3

Suggestive Evidence

Single association study (PMID: 19598235), not significant if corrected for multiple testing.

Score Delta: Score remained at 4

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.

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Single association study (PMID: 19598235), not significant if corrected for multiple testing.

Reports Added
[New Scoring Scheme]
7/1/2016
4
icon
4

Decreased from 4 to 4

Description

Single association study (PMID: 19598235), not significant if corrected for multiple testing.

7/1/2014
No data
icon
4

Increased from No data to 4

Description

Single association study (PMID: 19598235), not significant if corrected for multiple testing.

4/1/2014
No data
icon
4

Increased from No data to 4

Description

Single association study (PMID: 19598235), not significant if corrected for multiple testing.

Krishnan Probability Score

Score 0.78580128296318

Ranking 4/25841 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 0.97853623842781

Ranking 2179/18225 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
Sanders TADA Score

Score 0.94884392936079

Ranking 17849/18665 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).
Larsen Cumulative Evidence Score

Score 2

Ranking 402/461 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.
Zhang D Score

Score 0.28809044352341

Ranking 2911/20870 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
IRAK3 interleukin-1 receptor-associated kinase 3 Human Protein Binding 11213 Q9Y616
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