Human Gene Module / Chromosome 12 / PTPN11

PTPN11protein tyrosine phosphatase, non-receptor type 11

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
8 / 27
Rare Variants / Common Variants
44 / 0
Aliases
PTPN11, BPTP3,  CFC,  MGC14433,  NS1,  PTP-1D,  PTP2C,  SH-PTP2,  SH-PTP3,  SHP2
Associated Syndromes
Noonan syndrome, Noonan syndrome 1
Chromosome Band
12q24.13
Associated Disorders
DD/NDD, ID, EP, EPS, ASD
Relevance to Autism

This gene has been associated with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. In particular, rare mutations of the PTPN11 gene have been identified with Noonan syndrome (Tartaglia et al., 2001).

Molecular Function

The protein encoded by this gene is a member of the protein tyrosine phosphatase (PTP) family. This PTP contains two tandem Src homology-2 domains, which function as phospho-tyrosine binding domains and mediate the interaction of this PTP with its substrates. This PTP is widely expressed in most tissues and plays a regulatory role in various cell signaling events that are important for a diversity of cell functions, such as mitogenic activation, metabolic control, transcription regulation, and cell migration. Mutations in this gene are a cause of Noonan syndrome as well as acute myeloid leukemia.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to PTPN11 (27 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome Tartaglia M , et al. (2001) No ASD
2 Recent Recommendation Autism traits in the RASopathies Adviento B , et al. (2013) No Autistic features
3 Recent Recommendation Behavioral profile in RASopathies Alfieri P , et al. (2014) No Autistic features
4 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
5 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No ASD, DD
6 Support Excess of rare, inherited truncating mutations in autism Krumm N , et al. (2015) Yes -
7 Recent Recommendation De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies Homsy J , et al. (2016) No DD, learning disabilities
8 Support High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing Martnez F , et al. (2016) No ID
9 Support Clinical exome sequencing: results from 2819 samples reflecting 1000 families Trujillano D , et al. (2016) No -
10 Support Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains Geisheker MR , et al. (2017) Yes -
11 Support Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands Jin SC , et al. (2017) No Neurodevelopmental disorders (NDD)
12 Support Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder Takata A , et al. (2018) Yes -
13 Support PTPN11 Gain-of-Function Mutations Affect the Developing Human Brain, Memory, and Attention Johnson EM , et al. (2018) No -
14 Support Elucidation of the phenotypic spectrum and genetic landscape in primary and secondary microcephaly Boonsawat P , et al. (2019) No DD, epilepsy/seizures
15 Support Variant recurrence in neurodevelopmental disorders: the use of publicly available genomic data identifies clinically relevant pathogenic missense variants Lecoquierre F , et al. (2019) No -
16 Support Comprehensive Analysis of Rare Variants of 101 Autism-Linked Genes in a Hungarian Cohort of Autism Spectrum Disorder Patients Balicza P , et al. (2019) Yes -
17 Support - Brunet T et al. (2021) No Epilepsy/seizures, autistic features
18 Support - Valentino F et al. (2021) No DD
19 Support - Rosenthal SB et al. (2021) Yes -
20 Support - Pode-Shakked B et al. (2021) No -
21 Support - Brea-Fernández AJ et al. (2022) No -
22 Support - Leite AJDC et al. (2022) No -
23 Support - Zhou X et al. (2022) Yes -
24 Support - Rai B et al. (2023) No -
25 Support - Tuncay IO et al. (2023) Yes -
26 Support - Sanchis-Juan A et al. (2023) No -
27 Support - et al. () No -
Rare Variants   (44)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.328G>A p.Glu110Lys missense_variant De novo - Simplex 38041506 et al. ()
c.1391G>C p.Ser464Thr missense_variant De novo - Simplex 38041506 et al. ()
c.9G>A p.Ser3%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.182A>G p.Asp61Gly missense_variant - - - 11704759 Tartaglia M , et al. (2001)
c.188A>G p.Tyr63Cys missense_variant - - - 11704759 Tartaglia M , et al. (2001)
c.215C>G p.Ala72Gly missense_variant - - - 11704759 Tartaglia M , et al. (2001)
c.228G>C p.Glu76Asp missense_variant - - - 11704759 Tartaglia M , et al. (2001)
c.844A>G p.Ile282Val missense_variant - - - 11704759 Tartaglia M , et al. (2001)
c.922A>G p.Asn308Asp missense_variant - - - 11704759 Tartaglia M , et al. (2001)
c.577C>G p.Leu193Val missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.184T>G p.Tyr62Asp missense_variant De novo - - 28991257 Jin SC , et al. (2017)
c.1510A>G p.Met504Val missense_variant - - - 11704759 Tartaglia M , et al. (2001)
c.221T>G p.Leu74Trp missense_variant De novo - - 26785492 Homsy J , et al. (2016)
c.1517C>T p.Ser506Leu missense_variant De novo - - 28991257 Jin SC , et al. (2017)
c.802G>T p.Gly268Cys missense_variant De novo - - 26785492 Homsy J , et al. (2016)
c.922A>G p.Asn308Asp missense_variant De novo - - 26785492 Homsy J , et al. (2016)
c.1520G>A p.Gly507Glu missense_variant De novo - - 26785492 Homsy J , et al. (2016)
c.182A>G p.Asp61Gly missense_variant De novo - - 27620904 Martnez F , et al. (2016)
c.854T>C p.Phe285Ser missense_variant De novo - - 35390071 Leite AJDC et al. (2022)
c.1471C>A p.Pro491Thr missense_variant De novo - - 34356170 Valentino F et al. (2021)
c.854T>C p.Phe285Ser missense_variant De novo - - 27848944 Trujillano D , et al. (2016)
c.1529A>G p.Gln510Arg missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.166A>G p.Ile56Val missense_variant De novo - Unknown 33619735 Brunet T et al. (2021)
c.1611+374C>T - intron_variant Familial Both parents - 37492102 Tuncay IO et al. (2023)
c.1472C>A p.Pro491His missense_variant Unknown - - 28628100 Geisheker MR , et al. (2017)
c.1492C>T p.Arg498Trp missense_variant Unknown - - 28628100 Geisheker MR , et al. (2017)
c.1496C>T p.Ser499Phe missense_variant Unknown - - 28628100 Geisheker MR , et al. (2017)
c.1546A>G p.Met516Val missense_variant Unknown - - 28628100 Geisheker MR , et al. (2017)
c.1520G>A p.Gly507Glu missense_variant De novo - Simplex 25961944 Krumm N , et al. (2015)
c.1510A>G p.Met504Val missense_variant De novo - Unknown 33619735 Brunet T et al. (2021)
c.417G>C p.Glu139Asp missense_variant De novo - Multiplex 33619735 Brunet T et al. (2021)
c.1403C>T p.Thr468Met missense_variant De novo - Simplex 29346770 Takata A , et al. (2018)
c.1502G>A p.Arg501Lys stop_gained Unknown Not maternal - 31134136 Balicza P , et al. (2019)
c.923A>G p.Asn308Ser missense_variant De novo - Simplex 30842647 Boonsawat P , et al. (2019)
c.214G>T p.Ala72Ser missense_variant Familial - Multiplex 11704759 Tartaglia M , et al. (2001)
c.923A>G p.Asn308Ser missense_variant De novo - Simplex 34580403 Pode-Shakked B et al. (2021)
c.417G>C p.Glu139Asp missense_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.1507G>C p.Gly503Arg missense_variant De novo - - 35322241 Brea-Fernández AJ et al. (2022)
c.1230del p.Leu411SerfsTer65 intron_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.236A>G p.Gln79Arg missense_variant Familial Paternal Multiplex 11704759 Tartaglia M , et al. (2001)
c.1508G>A p.Gly503Glu missense_variant Familial Paternal Multiplex 28628100 Geisheker MR , et al. (2017)
c.184T>G p.Tyr62Asp missense_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.1508G>A p.Gly503Glu missense_variant Familial Maternal Multi-generational 31036916 Lecoquierre F , et al. (2019)
c.1507G>A p.Gly503Arg missense_variant De novo - Multiplex 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 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.

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."

1/1/2021
1
icon
1

Score remained at 1

Description

This gene is associated with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. In particular, rare mutations of the PTPN11 gene have been identified with patients with Noonan syndrome (PMID 11704759). The prevalence of autistic traits in patients with Noonan syndrome has been quantified using standard assessment tools (PMIDs 24101678, 24458522). A de novo missense variant in the PTPN11 gene was identified in an ASD proband from the Simons Simplex Collection; no de novo SNVs in this gene were observed in unaffected SSC siblings (P=0.05) (PMID 25961944). The proteins encoded by PTPN11 and the high-confidence ASD gene MET interact with each other (PMID 8662733).

Reports Added
[De novo variants in neurodevelopmental disorders-experiences from a tertiary care center2021]
10/1/2019
4S
icon
1

Decreased from 4S to 1

New Scoring Scheme
Description

This gene is associated with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. In particular, rare mutations of the PTPN11 gene have been identified with patients with Noonan syndrome (PMID 11704759). The prevalence of autistic traits in patients with Noonan syndrome has been quantified using standard assessment tools (PMIDs 24101678, 24458522). A de novo missense variant in the PTPN11 gene was identified in an ASD proband from the Simons Simplex Collection; no de novo SNVs in this gene were observed in unaffected SSC siblings (P=0.05) (PMID 25961944). The proteins encoded by PTPN11 and the high-confidence ASD gene MET interact with each other (PMID 8662733).

Reports Added
[New Scoring Scheme]
7/1/2019
4S
icon
4S

Decreased from 4S to 4S

Description

This gene is associated with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. In particular, rare mutations of the PTPN11 gene have been identified with patients with Noonan syndrome (PMID 11704759). The prevalence of autistic traits in patients with Noonan syndrome has been quantified using standard assessment tools (PMIDs 24101678, 24458522). A de novo missense variant in the PTPN11 gene was identified in an ASD proband from the Simons Simplex Collection; no de novo SNVs in this gene were observed in unaffected SSC siblings (P=0.05) (PMID 25961944). The proteins encoded by PTPN11 and the high-confidence ASD gene MET interact with each other (PMID 8662733).

Reports Added
[Variantrecurrence in neurodevelopmental disorders: the use of publicly available genomic data identifies clinically relevant pathogenic missense v...2019] [Comprehensive Analysis of Rare Variants of 101 Autism-Linked Genes in a Hungarian Cohort of Autism Spectrum Disorder Patients.2019]
4/1/2019
4S
icon
4S

Decreased from 4S to 4S

Description

This gene is associated with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. In particular, rare mutations of the PTPN11 gene have been identified with patients with Noonan syndrome (PMID 11704759). The prevalence of autistic traits in patients with Noonan syndrome has been quantified using standard assessment tools (PMIDs 24101678, 24458522). A de novo missense variant in the PTPN11 gene was identified in an ASD proband from the Simons Simplex Collection; no de novo SNVs in this gene were observed in unaffected SSC siblings (P=0.05) (PMID 25961944). The proteins encoded by PTPN11 and the high-confidence ASD gene MET interact with each other (PMID 8662733).

Reports Added
[Elucidation of the phenotypic spectrum and genetic landscape in primary and secondary microcephaly.2019]
7/1/2018
4S
icon
4S

Decreased from 4S to 4S

Description

This gene is associated with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. In particular, rare mutations of the PTPN11 gene have been identified with patients with Noonan syndrome (PMID 11704759). The prevalence of autistic traits in patients with Noonan syndrome has been quantified using standard assessment tools (PMIDs 24101678, 24458522). A de novo missense variant in the PTPN11 gene was identified in an ASD proband from the Simons Simplex Collection; no de novo SNVs in this gene were observed in unaffected SSC siblings (P=0.05) (PMID 25961944). The proteins encoded by PTPN11 and the high-confidence ASD gene MET interact with each other (PMID 8662733).

Reports Added
[PTPN11 Gain-of-Function Mutations Affect the Developing Human Brain, Memory, and Attention.2018]
10/1/2017
4S
icon
4S

Decreased from 4S to 4S

Description

This gene is associated with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. In particular, rare mutations of the PTPN11 gene have been identified with patients with Noonan syndrome (PMID 11704759). The prevalence of autistic traits in patients with Noonan syndrome has been quantified using standard assessment tools (PMIDs 24101678, 24458522). A de novo missense variant in the PTPN11 gene was identified in an ASD proband from the Simons Simplex Collection; no de novo SNVs in this gene were observed in unaffected SSC siblings (P=0.05) (PMID 25961944). The proteins encoded by PTPN11 and the high-confidence ASD gene MET interact with each other (PMID 8662733).

Reports Added
[Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands.2017]
7/1/2017
4S
icon
4S

Decreased from 4S to 4S

Description

This gene is associated with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. In particular, rare mutations of the PTPN11 gene have been identified with patients with Noonan syndrome (PMID 11704759). The prevalence of autistic traits in patients with Noonan syndrome has been quantified using standard assessment tools (PMIDs 24101678, 24458522). A de novo missense variant in the PTPN11 gene was identified in an ASD proband from the Simons Simplex Collection; no de novo SNVs in this gene were observed in unaffected SSC siblings (P=0.05) (PMID 25961944). The proteins encoded by PTPN11 and the high-confidence ASD gene MET interact with each other (PMID 8662733).

Reports Added
[Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains.2017]
10/1/2016
4S
icon
4S

Decreased from 4S to 4S

Description

This gene is associated with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. In particular, rare mutations of the PTPN11 gene have been identified with patients with Noonan syndrome (PMID 11704759). The prevalence of autistic traits in patients with Noonan syndrome has been quantified using standard assessment tools (PMIDs 24101678, 24458522). A de novo missense variant in the PTPN11 gene was identified in an ASD proband from the Simons Simplex Collection; no de novo SNVs in this gene were observed in unaffected SSC siblings (P=0.05) (PMID 25961944). The proteins encoded by PTPN11 and the high-confidence ASD gene MET interact with each other (PMID 8662733).

Reports Added
[High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing.2016] [Clinical exome sequencing: results from 2819 samples reflecting 1000 families.2016]
1/1/2016
4S
icon
4S

Decreased from 4S to 4S

Description

This gene is associated with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. In particular, rare mutations of the PTPN11 gene have been identified with patients with Noonan syndrome (PMID 11704759). The prevalence of autistic traits in patients with Noonan syndrome has been quantified using standard assessment tools (PMIDs 24101678, 24458522). A de novo missense variant in the PTPN11 gene was identified in an ASD proband from the Simons Simplex Collection; no de novo SNVs in this gene were observed in unaffected SSC siblings (P=0.05) (PMID 25961944). The proteins encoded by PTPN11 and the high-confidence ASD gene MET interact with each other (PMID 8662733).

Reports Added
[Large-scale discovery of novel genetic causes of developmental disorders.2014] [Autism traits in the RASopathies.2013] [Behavioral profile in RASopathies.2014] [Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome.2001] [Excess of rare, inherited truncating mutations in autism.2015] [The contribution of de novo coding mutations to autism spectrum disorder2014] [De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies.2016]
7/1/2015
5
icon
4S

Decreased from 5 to 4S

Description

This gene is associated with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. In particular, rare mutations of the PTPN11 gene have been identified with patients with Noonan syndrome (PMID 11704759). The prevalence of autistic traits in patients with Noonan syndrome has been quantified using standard assessment tools (PMIDs 24101678, 24458522). A de novo missense variant in the PTPN11 gene was identified in an ASD proband from the Simons Simplex Collection; no de novo SNVs in this gene were observed in unaffected SSC siblings (P=0.05) (PMID 25961944). The proteins encoded by PTPN11 and the high-confidence ASD gene MET interact with each other (PMID 8662733).

4/1/2015
5
icon
5

Decreased from 5 to 5

Description

This gene has been associated with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. In particular, rare mutations of the PTPN11 gene have been identified with Noonan syndrome (PMID 11704759).

Reports Added
[Excess of rare, inherited truncating mutations in autism.2015]
1/1/2015
5
icon
5

Decreased from 5 to 5

Description

This gene has been associated with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. In particular, rare mutations of the PTPN11 gene have been identified with Noonan syndrome (PMID 11704759).

Reports Added
[Large-scale discovery of novel genetic causes of developmental disorders.2014]
7/1/2014
No data
icon
5

Increased from No data to 5

Description

This gene has been associated with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. In particular, rare mutations of the PTPN11 gene have been identified with Noonan syndrome (PMID 11704759).

4/1/2014
No data
icon
5

Increased from No data to 5

Description

This gene has been associated with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. In particular, rare mutations of the PTPN11 gene have been identified with Noonan syndrome (PMID 11704759).

Reports Added
[Autism traits in the RASopathies.2013] [Behavioral profile in RASopathies.2014]
Krishnan Probability Score

Score 0.45429159814388

Ranking 10178/25841 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 0.99987723087868

Ranking 711/18225 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 0.74337448425131

Ranking 1491/18665 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 0.009701573082835

Ranking 8368/20870 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
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
C-MET Hepatocyte growth factor receptor Human Protein Binding 4233 P08581
GPX7 Glutathione peroxidase 7 Human Protein Binding 2882 Q96SL4
LUM Lumican Human Protein Binding 4060 P51884
PDCD1 Programmed cell death protein 1 Human Protein Binding 5133 Q15116
TCEAL1 Transcription elongation factor A protein-like 1 Human Protein Binding 9338 Q15170-2
TMEM220 Transmembrane protein 220 Human Protein Binding 388335 Q6QAJ8-2
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