Human Gene Module / Chromosome 12 / PTPN11

PTPN11protein tyrosine phosphatase, non-receptor type 11

Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
5 / 16
Rare Variants / Common Variants
30 / 0
Aliases
PTPN11, BPTP3,  CFC,  MGC14433,  NS1,  PTP-1D,  PTP2C,  SH-PTP2,  SH-PTP3,  SHP2
Associated Syndromes
Noonan syndrome
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
12q24.13
Associated Disorders
ASD, ID, DD/NDD, EPS
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.

Reports related to PTPN11 (16 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 Variantrecurrence in neurodevelopmental disorders: the use of publicly available genomic data identifies clinically relevant pathogenic missense v... 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 -
Rare Variants   (30)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
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.1510A>G p.Met504Val missense_variant - - - 11704759 Tartaglia M , et al. (2001)
c.184T>G p.Tyr62Asp missense_variant De novo NA - 28991257 Jin SC , et al. (2017)
c.221T>G p.Leu74Trp missense_variant De novo NA - 26785492 Homsy J , et al. (2016)
c.1517C>T p.Ser506Leu missense_variant De novo NA - 28991257 Jin SC , et al. (2017)
c.802G>T p.Gly268Cys missense_variant De novo NA - 26785492 Homsy J , et al. (2016)
c.922A>G p.Asn308Asp missense_variant De novo NA - 26785492 Homsy J , et al. (2016)
c.1520G>A p.Gly507Glu missense_variant De novo NA - 26785492 Homsy J , et al. (2016)
c.182A>G p.Asp61Gly missense_variant De novo NA - 27620904 Martnez F , et al. (2016)
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.854T>C p.Phe285Ser missense_variant De novo NA - 27848944 Trujillano D , et al. (2016)
c.1520G>A p.Gly507Glu missense_variant De novo NA Simplex 25961944 Krumm N , et al. (2015)
c.1502G>A p.Arg501Lys stop_gained Unknown Not maternal - 31134136 Balicza P , et al. (2019)
c.1403C>T p.Thr468Met missense_variant De novo NA Simplex 29346770 Takata A , et al. (2018)
c.923A>G p.Asn308Ser missense_variant De novo NA Simplex 30842647 Boonsawat P , et al. (2019)
c.214G>T p.Ala72Ser missense_variant Familial - Multiplex 11704759 Tartaglia M , et al. (2001)
c.1230del p.Leu411SerfsTer65 intron_variant De novo NA 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 NA 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 NA Multiplex 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

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).

Score Delta: Decreased from 4S to 1

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.

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).

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).

7/1/2018
4.4 + S
icon
4S

Decreased from 4.4 + S 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).

4/1/2018
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).

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).

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).

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).

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).

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).

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).

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.
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
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).
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.
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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