Human Gene Module / Chromosome 9 / NTRK2

NTRK2neurotrophic receptor tyrosine kinase 2

SFARI Gene Score
S
Syndromic Syndromic
Autism Reports / Total Reports
5 / 10
Rare Variants / Common Variants
21 / 0
Aliases
NTRK2, GP145-TrkB,  OBHD,  TRKB,  trk-B
Associated Syndromes
-
Chromosome Band
9q21.33
Associated Disorders
DD/NDD, ID, ASD
Relevance to Autism

A recurrent de novo missense variant in the NTRK2 gene (;p.Tyr434Cys) was identified in four individuals presenting with epilepsy and developmental delay/intellectual disability; two of these individuals were also diagnosed with ASD (Hamdan et al., 2017). An fifth individual found to have a de novo NTRK2 missense variant (p.Thr720Ile) was also reported in Hamdan et al., 2017; this case was diagnosed with ASD and presented with epilepsy, global developmental delay, and intellectual disability.

Molecular Function

This gene encodes a member of the neurotrophic tyrosine receptor kinase (NTRK) family. This kinase is a membrane-bound receptor that, upon neurotrophin binding, phosphorylates itself and members of the MAPK pathway. Signalling through this kinase leads to cell differentiation. Mutations in this gene are associated with obesity, hyperphagia, and developmental delay (OBHD; OMIM 613886); affected individuals have been reported to display stereotyped behaviors and repetitive speech (Yeo et al., 2004) and ritualized behaviors (Miller et al., 2017).

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to NTRK2 (10 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support A de novo mutation affecting human TrkB associated with severe obesity and developmental delay Yeo GS , et al. (2004) No Stereotyped behaviors, repetitive speech
2 Support Diagnostic value of exome and whole genome sequencing in craniosynostosis Miller KA , et al. (2016) No Ritualized behaviors
3 Primary High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies Hamdan FF , et al. (2017) No DD, ID, ASD
4 Support - Yoganathan S et al. (2021) No Autistic features
5 Support - Long A et al. (2022) No ASD
6 Support - Tuncay IO et al. (2022) Yes DD
7 Support - Woodbury-Smith M et al. (2022) Yes -
8 Support - Zhou X et al. (2022) Yes -
9 Support - Soo-Whee Kim et al. (2024) Yes -
10 Support - Hosneara Akter et al. () Yes -
Rare Variants   (21)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.220G>A p.Ala74Thr missense_variant Unknown - - 15494731 Yeo GS , et al. (2004)
c.292A>G p.Ile98Val missense_variant Unknown - - 15494731 Yeo GS , et al. (2004)
c.1555A>G p.Ile519Val missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1060A>G p.Met354Val missense_variant Unknown - - 15494731 Yeo GS , et al. (2004)
c.1979C>T p.Pro660Leu missense_variant Unknown - - 15494731 Yeo GS , et al. (2004)
c.1301A>G p.Tyr434Cys missense_variant De novo - - 29100083 Hamdan FF , et al. (2017)
- - intergenic_variant Familial Both parents Simplex 35190550 Tuncay IO et al. (2022)
c.694G>T p.Val232Phe missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1301A>G p.Tyr434Cys missense_variant De novo - - 34425480 Yoganathan S et al. (2021)
c.1652G>A p.Arg551Gln missense_variant De novo - - 34425480 Yoganathan S et al. (2021)
c.2234G>A p.Arg745Gln missense_variant De novo - - 39334436 Soo-Whee Kim et al. (2024)
c.1529C>T p.Ser510Leu missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.2165A>G p.Tyr722Cys missense_variant De novo - Simplex 15494731 Yeo GS , et al. (2004)
c.1882C>A p.Pro628Thr missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.1887C>T p.Leu629%3D synonymous_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.2413_2414delinsCT p.Thr805Leu missense_variant Unknown - - 15494731 Yeo GS , et al. (2004)
c.1330G>T p.Gly444Ter stop_gained Unknown Not maternal - 27884935 Miller KA , et al. (2016)
c.1301A>G p.Tyr434Cys missense_variant De novo - Simplex 29100083 Hamdan FF , et al. (2017)
c.2159C>T p.Thr720Ile missense_variant De novo - Simplex 29100083 Hamdan FF , et al. (2017)
c.1301A>G p.Tyr434Cys missense_variant Unknown - Simplex 34425480 Yoganathan S et al. (2021)
c.970_986del p.Leu324HisfsTer4 frameshift_variant Unknown - - 39342494 Hosneara Akter et al. ()
Common Variants  

No common variants reported.

SFARI Gene score
S

Syndromic

A recurrent de novo missense variant in the NTRK2 gene (p.Tyr434Cys) was identified in four individuals presenting with epilepsy and developmental delay/intellectual disability; two of these individuals were also diagnosed with ASD (Hamdan et al., 2017). An fifth individual found to have a de novo NTRK2 missense variant (p.Thr720Ile) was also reported in Hamdan et al., 2017; this case was diagnosed with ASD and presented with epilepsy, global developmental delay, and intellectual disability. Mutations in the NTRK2 gene have previously been associated with obesity, hyperphagia, and developmental delay (OBHD; OMIM 613886); affected individuals have been reported to display stereotyped behaviors and repetitive speech (Yeo et al., 2004) and ritualized behaviors (Miller et al., 2017).

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."

10/1/2019
S
icon
S

Score remained at S

New Scoring Scheme
Description

A recurrent de novo missense variant in the NTRK2 gene (p.Tyr434Cys) was identified in four individuals presenting with epilepsy and developmental delay/intellectual disability; two of these individuals were also diagnosed with ASD (Hamdan et al., 2017). An fifth individual found to have a de novo NTRK2 missense variant (p.Thr720Ile) was also reported in Hamdan et al., 2017; this case was diagnosed with ASD and presented with epilepsy, global developmental delay, and intellectual disability. Mutations in the NTRK2 gene have previously been associated with obesity, hyperphagia, and developmental delay (OBHD; OMIM 613886); affected individuals have been reported to display stereotyped behaviors and repetitive speech (Yeo et al., 2004) and ritualized behaviors (Miller et al., 2017).

Reports Added
[New Scoring Scheme]
Krishnan Probability Score

Score 0.76432044032504

Ranking 28/25841 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 0.9998931800982

Ranking 684/18225 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 0.93873744788382

Ranking 13966/18665 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 -0.090133616300506

Ranking 11976/20870 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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