Human Gene Module / Chromosome 2 / PTPN4

PTPN4protein tyrosine phosphatase non-receptor type 4

SFARI Gene Score
S
Syndromic Syndromic
Autism Reports / Total Reports
2 / 5
Rare Variants / Common Variants
10 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
2q14.2
Associated Disorders
-
Relevance to Autism

Chmielewska et al., 2021 reported six unrelated individuals with missense or protein-truncating variants in the PTPN4 gene who exhibited varying degrees of intellectual disability or developmental delay; two of these individuals presented with autism spectrum disorder, and the missense variant identified in one of these individuals with ASD (p.Gly239Arg in patient 1 in this report) was shown experimentally to result in failure of PTPN4 to localize to the dendritic spines of transfected rat hippocampal neurons, in contrast to WT PTPN4. Mutations in PTPN4 had previously been identifed in monozygotic twins presenting with a Rett syndrome-like phenotype characterized by developmental delay, seizures, and stereotypic hand movements (Williamson et al., 2015), as well as in a child presenting with developmental delay, autistic features, and upper limb stereotypies (Szczauba et al., 2018).

Molecular Function

The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This protein contains a C-terminal PTP domain and an N-terminal domain homologous to the band 4.1 superfamily of cytoskeletal-associated proteins. This PTP has been shown to interact with glutamate receptor delta 2 and epsilon subunits, and is thought to play a role in signalling downstream of the glutamate receptors through tyrosine dephosphorylation.

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Reports related to PTPN4 (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support - Williamson SL et al. (2015) No Stereotypy
2 Support - Szczałuba K et al. (2018) No Autistic features, stereotypy
3 Primary - Chmielewska JJ et al. (2021) No ASD, ADHD, epilepsy/seizures
4 Support - Zhou X et al. (2022) Yes -
5 Support - Sheth F et al. (2023) Yes DD, ID
Rare Variants   (10)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1171C>T p.Arg391Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.2512C>T p.Arg838Ter stop_gained Unknown - - 34527963 Chmielewska JJ et al. (2021)
c.191T>G p.Leu64Trp missense_variant De novo - - 34527963 Chmielewska JJ et al. (2021)
c.215T>C p.Leu72Ser missense_variant De novo - - 30238967 Szczałuba K et al. (2018)
c.2171T>C p.Ile724Thr missense_variant De novo - - 34527963 Chmielewska JJ et al. (2021)
- - copy_number_loss De novo - Multiplex (monozygotic twins) 25424712 Williamson SL et al. (2015)
c.715G>A p.Gly239Arg missense_variant De novo - Multiplex 34527963 Chmielewska JJ et al. (2021)
c.2619A>T p.Glu873Asp missense_variant Familial Maternal Simplex 37543562 Sheth F et al. (2023)
c.1738G>T p.Asp580Tyr missense_variant De novo - Multiplex 34527963 Chmielewska JJ et al. (2021)
c.393_396del p.Gln132ThrfsTer17 frameshift_variant De novo - - 34527963 Chmielewska JJ et al. (2021)
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 0.49588872122573

Ranking 2761/25841 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 0.99999751600417

Ranking 358/18225 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
Zhang D Score

Score -0.19869658821521

Ranking 15395/20870 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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