Human Gene Module / Chromosome 10 / PTEN

PTENphosphatase and tensin homolog (mutated in multiple advanced cancers 1)

Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
18 / 46
Rare Variants / Common Variants
66 / 0
Aliases
PTEN, BZS,  MHAM,  TEP1,  MMAC1,  PTEN1,  MGC11227
Associated Syndromes
Macrocephaly/autism syndrome, Cowden syndrome
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
10q23.31
Associated Disorders
ADHD, ID, ASD, DD/NDD, EPS
Relevance to Autism

Recurrent mutations in the PTEN gene have been identified in multiple individuals with ASD as described below. Deleterious variants in PTEN have been identified in individuals presenting with ASD and macrocephaly in multiple studies (PMIDs 15805158, 18759867, 19265751, 20533527). Two de novo deleterious events in the PTEN gene were identified in exome sequencing studies in simplex ASD cases in 2012: a missense variant (p.Thr167Asn) that was classified as "severe" in O'Roak et al. Nature 2012 (PMID 22495309); and a frameshift variant (p.Cys136MetfsX44) in O'Roak et al. Science 2012 (PMID 23160955). A detailed examination of ASD cases with heterozygous PTEN mutations in Frazier et al., 2015 found that these cases had a high proportion of missense variants, showed reduced PTEN protein levels, and exhibited prominent white-matter and cognitive abnormalities compared to other groups (PMID 25288137). An additional de novo loss-of-function variant in the PTEN gene was subsequently identified in an ASD proband from 2,270 trios screened by the Autism Sequencing Consortium in De Rubeis et al., 2014 (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in this report furthermore identified PTEN as a gene meeting high statistical significance with a 0.01 < FDR ≤ 0.05, meaning that this gene had a ≥ 95% chance of being a true autism gene. This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). PTEN has also been designated as a syndromic ASD gene, as mutations in the PTEN gene are causative for Cowden syndrome, a disorder in which a subpopulation of individuals with the syndrome develop autism (PMID 11496368).

Molecular Function

The protein encoded this gene is a phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase. It contains a tensin like domain as well as a catalytic domain similar to that of the dual specificity protein tyrosine phosphatases.

Reports related to PTEN (46 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary PTEN mutation in a family with Cowden syndrome and autism. Goffin A , et al. (2001) No ASD
2 Positive Association Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations. Butler MG , et al. (2005) Yes ASD, macrocephaly
3 Recent Recommendation Electrical signals control wound healing through phosphatidylinositol-3-OH kinase-gamma and PTEN. Zhao M , et al. (2006) No -
4 Recent Recommendation Free fatty acids inhibit insulin signaling-stimulated endothelial nitric oxide synthase activation through upregulating PTEN or inhibiting Akt kinase. Wang XL , et al. (2006) No -
5 Support Mutation screening of the PTEN gene in patients with autism spectrum disorders and macrocephaly. Buxbaum JD , et al. (2007) Yes -
6 Support Novel PTEN mutations in neurodevelopmental disorders and macrocephaly. Orrico A , et al. (2008) Yes DD, ID
7 Support The prevalence of PTEN mutations in a clinical pediatric cohort with autism spectrum disorders, developmental delay, and macrocephaly. Varga EA , et al. (2009) Yes -
8 Support Confirmation study of PTEN mutations among individuals with autism or developmental delays/mental retardation and macrocephaly. McBride KL , et al. (2010) Yes -
9 Recent Recommendation PTEN is recruited to the postsynaptic terminal for NMDA receptor-dependent long-term depression. Jurado S , et al. (2010) No -
10 Support A mutant form of PTEN linked to autism. Redfern RE , et al. (2010) No -
11 Support Autistic spectrum disorder in a 9-year-old girl with macrocephaly. Stein MT , et al. (2010) Yes -
12 Support Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders. Schaaf CP , et al. (2011) Yes -
13 Support Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. O'Roak BJ , et al. (2012) Yes -
14 Support Novel PTEN germline mutation in a family with mild phenotype: difficulties in genetic counseling. Busa T , et al. (2012) No ID
15 Support Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. O'Roak BJ , et al. (2012) Yes -
16 Support Biochemical screening and PTEN mutation analysis in individuals with autism spectrum disorders and macrocephaly. Hobert JA , et al. (2013) Yes DD, epilepsy
17 Recent Recommendation A secreted PTEN phosphatase that enters cells to alter signaling and survival. Hopkins BD , et al. (2013) No -
18 Positive association De novo mutations in epileptic encephalopathies. Epi4K Consortium , et al. (2013) No IS, LGS, DD, ID, ASD, ADHD
19 Recent Recommendation PTEN knockdown alters dendritic spine/protrusion morphology, not density. Haws ME , et al. (2013) No -
20 Recent Recommendation Characteristic brain magnetic resonance imaging pattern in patients with macrocephaly and PTEN mutations. Vanderver A , et al. (2014) No -
21 Recent Recommendation Loss of mTOR repressors Tsc1 or Pten has divergent effects on excitatory and inhibitory synaptic transmission in single hippocampal neuron cultures. Weston MC , et al. (2014) No -
22 Support Autism-epilepsy phenotype with macrocephaly suggests PTEN, but not GLIALCAM, genetic screening. Marchese M , et al. (2014) Yes ID, epilepsy
23 Recent recommendation PTEN interacts with histone H1 and controls chromatin condensation. Chen ZH , et al. (2014) No -
24 Recent recommendation Molecular and phenotypic abnormalities in individuals with germline heterozygous PTEN mutations and autism. Frazier TW , et al. (2014) No -
25 Recent recommendation Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
26 Recent recommendation Functionally distinct groups of inherited PTEN mutations in autism and tumour syndromes. Spinelli L , et al. (2014) No -
27 Recent recommendation Conformational stability and catalytic activity of PTEN variants linked to cancers and autism spectrum disorders. Johnston SB and Raines RT (2015) No -
28 Recent recommendation Neural transcriptome of constitutional Pten dysfunction in mice and its relevance to human idiopathic autism spectrum disorder. Tilot AK , et al. (2015) No -
29 Recent recommendation The parvalbumin/somatostatin ratio is increased in Pten mutant mice and by human PTEN ASD alleles. Vogt D , et al. (2015) No -
30 Support Excess of rare, inherited truncating mutations in autism. Krumm N , et al. (2015) Yes -
31 Support Integrated analysis of whole-exome sequencing and transcriptome profiling in males with autism spectrum disorders. Codina-Sol M , et al. (2015) Yes -
32 Support Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder. Tammimies K , et al. (2015) No -
33 Recent recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
34 Support A recessive form of extreme macrocephaly and mild intellectual disability complements the spectrum of PTEN hamartoma tumour syndrome. Schwerd T , et al. (2015) No -
35 Recent recommendation Autistic-Like Traits and Cerebellar Dysfunction in Purkinje Cell PTEN Knock-Out Mice. Cupolillo D , et al. (2015) No -
36 Support Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms. D'Gama AM , et al. (2015) Yes -
37 Recent recommendation A Retroviral CRISPR-Cas9 System for Cellular Autism-Associated Phenotype Discovery in Developing Neurons. Williams MR , et al. (2016) No -
38 Support A combination of genetic and biochemical analyses for the diagnosis of PI3K-AKT-mTOR pathway-associated megalencephaly. Negishi Y , et al. (2017) No -
39 Support Prevalence of four Mendelian disorders associated with autism in 2392 affected families. Saskin A , et al. (2017) Yes -
40 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. C Yuen RK , et al. (2017) Yes -
41 Support PTEN Loss Increases the Connectivity of Fast Synaptic Motifs and Functional Connectivity in a Developing Hippocampal Network. Barrows CM , et al. (2017) No -
42 Support Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test. Lionel AC , et al. (2017) No -
43 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)
44 Highly Cited PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Li J , et al. (1997) No -
45 Highly Cited The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. Maehama T and Dixon JE (1998) No -
46 Highly Cited Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Stambolic V , et al. (1998) No -
Rare Variants   (66)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.534T>G p.Tyr178Ter stop_gained Familial Maternal - 11496368 Goffin A , et al. (2001)
c.278A>G p.His93Arg missense_variant De novo - Simplex 15805158 Butler MG , et al. (2005)
c.755A>G p.Asp252Gly missense_variant De novo - Simplex 15805158 Butler MG , et al. (2005)
c.722T>C p.Phe241Ser missense_variant De novo - Simplex 15805158 Butler MG , et al. (2005)
c.-1088C>T - 5_prime_UTR_variant - - - 17427195 Buxbaum JD , et al. (2007)
c.-1048C>T - 5_prime_UTR_variant Familial Maternal Multiplex 17427195 Buxbaum JD , et al. (2007)
c.-1026C>A - 5_prime_UTR_variant Familial Maternal - 17427195 Buxbaum JD , et al. (2007)
c.-903G>A - 5_prime_UTR_variant - - - 17427195 Buxbaum JD , et al. (2007)
c.-903G>A - 5_prime_UTR_variant - - - 17427195 Buxbaum JD , et al. (2007)
c.66C>G p.Asp22Glu missense_variant Familial Paternal Multiplex 17427195 Buxbaum JD , et al. (2007)
T to C N/A intron_variant Familial Maternal - 17427195 Buxbaum JD , et al. (2007)
c.976G>A p.Asp326Asn missense_variant De novo - - 17427195 Buxbaum JD , et al. (2007)
c.353A>C p.His118Pro missense_variant De novo - - 18759867 Orrico A , et al. (2008)
c.527A>G p.Tyr176Cys missense_variant De novo - - 18759867 Orrico A , et al. (2008)
c.827A>G p.Asn276Ser missense_variant De novo - - 18759867 Orrico A , et al. (2008)
c.338C>T p.Arg130Ter stop_gained Familial Paternal Multi-generational 19265751 Varga EA , et al. (2009)
c.470A>G p.Glu157Gly missense_variant De novo - Multiplex (identical twins) 19265751 Varga EA , et al. (2009)
c.416T>A p.Leu139Ter stop_gained Familial Paternal Simplex 19265751 Varga EA , et al. (2009)
c.520insT - frameshift_variant De novo - - 19265751 Varga EA , et al. (2009)
C>G - intron_variant De novo - - 19265751 Varga EA , et al. (2009)
c.131G>A p.Gly44Asp missense_variant Unknown - Unknown 19265751 Varga EA , et al. (2009)
c.518G>A p.Arg173His missense_variant Familial Maternal Multi-generational 19265751 Varga EA , et al. (2009)
c.605C>T p.Thr202Ile missense_variant De novo - - 19265751 Varga EA , et al. (2009)
G>A - splice_site_variant Unknown - - 19265751 Varga EA , et al. (2009)
c.697C>T p.Arg233Ter stop_gained Unknown Not paternal Multi-generational 19265751 Varga EA , et al. (2009)
A>G - splice_site_variant Familial Paternal Multi-generational 19265751 Varga EA , et al. (2009)
c.369C>G p.His123Gln missense_variant Unknown - Unknown 20533527 McBride KL , et al. (2010)
c.518G>A p.Arg173His missense_variant Familial Paternal Multi-generational 20533527 McBride KL , et al. (2010)
c.821G>T p.Trp274Leu missense_variant Familial Maternal Multi-generational 20533527 McBride KL , et al. (2010)
c.401T>C p.Met134Thr missense_variant Familial Maternal Multi-generational 20533527 McBride KL , et al. (2010)
c.1003C>T p.Arg335Ter stop_gained De novo - - 20814261 Stein MT , et al. (2010)
c.232A>G p.Thr78Ala missense_variant De novo - Simplex 21624971 Schaaf CP , et al. (2011)
c.618C>G p.Phe206Leu missense_variant Unknown - Simplex 21624971 Schaaf CP , et al. (2011)
delTTAGT N/A copy_number_loss Unknown - Simplex 21624971 Schaaf CP , et al. (2011)
c.500C>A p.Thr167Asn missense_variant De novo - Simplex 22495309 O'Roak BJ , et al. (2012)
c.402G>C p.Met134Ile missense_variant Familial Maternal Multi-generational 23124040 Busa T , et al. (2012)
c.392C>T p.Thr131Ile missense_variant De novo - Simplex 23160955 O'Roak BJ , et al. (2012)
c.405dupA p.Cys136MetfsTer44 frameshift_variant De novo - Simplex 23160955 O'Roak BJ , et al. (2012)
c.640C>T p.Gln214Ter stop_gained Familial Maternal Simplex 23160955 O'Roak BJ , et al. (2012)
c.420_421insA p.His141ThrfsTer39 frameshift_variant Unknown - Unknown 23695273 Hobert JA , et al. (2013)
c.208C>G p.Leu70Val missense_variant Unknown - Unknown 23695273 Hobert JA , et al. (2013)
c.3G>T p.Met1Ile initiator_codon_variant Unknown - Unknown 23695273 Hobert JA , et al. (2013)
c.1003C>T p.Arg335Ter stop_gained Unknown - Unknown 23695273 Hobert JA , et al. (2013)
c.209 + 5G>A - splice_site_variant Unknown - Unknown 23695273 Hobert JA , et al. (2013)
c.737C>T p.Pro246Leu missense_variant De novo - - 23934111 Epi4K Consortium , et al. (2013)
c.43delA p.Arg15AspfsTer9 frameshift_variant Unknown - - 24580998 Marchese M , et al. (2014)
c.493-1G>A p.? splice_site_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.619delA p.Ser207ValfsTer14 frameshift_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.400A>T p.Met134Leu missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.274G>A p.Asp92Asn missense_variant De novo - Simplex 25961944 Krumm N , et al. (2015)
c.239-21G>C - inframe_insertion De novo - Simplex 25969726 Codina-Sol M , et al. (2015)
c.494G>T p.Gly165Val missense_variant De novo - - 26325558 Tammimies K , et al. (2015)
c.[545T>C];[545T>C] p.[Leu182Ser];[Leu182Ser] missense_variant Familial Both parents Multiplex 26443266 Schwerd T , et al. (2015)
c.195C>A p.Tyr65Ter stop_gained Unknown - Unknown 26637798 D'Gama AM , et al. (2015)
c.640C>T p.Gln214Ter stop_gained Unknown Not maternal Simplex 28086757 Negishi Y , et al. (2017)
c.740T>C p.Leu247Ser missense_variant De novo - Simplex 28086757 Negishi Y , et al. (2017)
c.1006C>G p.Tyr336Ter stop_gained De novo - Simplex 28086757 Negishi Y , et al. (2017)
c.80-1G>A p.? splice_site_variant Familial Maternal - 28250423 Saskin A , et al. (2017)
c.149T>C p.Ile50Thr missense_variant Familial Maternal - 28250423 Saskin A , et al. (2017)
c.397G>A p.Val133Ile missense_variant Familial Maternal - 28250423 Saskin A , et al. (2017)
c.445C>T p.Gln149Ter stop_gained De novo - Simplex 28263302 C Yuen RK , et al. (2017)
c.132T>G;c.723T>G;c.1242T>G p.Phe44Leu;p.Phe241Leu;p.Phe414Leu missense_variant De novo - Simplex 28263302 C Yuen RK , et al. (2017)
c.132T>G;c.723T>G;c.1242T>G p.Phe44Leu;p.Phe241Leu;p.Phe414Leu missense_variant De novo - Simplex 28263302 C Yuen RK , et al. (2017)
c.737C>T p.Pro246Leu missense_variant De novo - Simplex 28263302 C Yuen RK , et al. (2017)
c.44G>T p.Arg15Ile missense_variant De novo - - 28771251 Lionel AC , et al. (2017)
T>G p.Tyr202Ter stop_gained De novo - - 28991257 Jin SC , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

Syndromic because of causative mutations in Cowden syndrome. Two de novo LGD events in PTEN from recent exome sequencing studies in simplex ASD cases: from O'Roak et al. Nature 2012 (PMID 22495309) a de novo missense variant (p.Thr167Asn) that was ranked severe"; and from O'Roak et al. Science 2012 (PMID 23160955) a de novo frameshift insertion (p.Cys136MetfsX44) was also identified." A de novo LoF variant in the PTEN gene was recently identified in an ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). A detailed examination of ASD cases with heterozygous PTEN mutations found that these cases had a high proportion of missense variants, showed reduced PTEN protein levels, and exhibited prominent white-matter and cognitive abnormalities compared to other groups (PMID 25288137). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified PTEN as a gene meeting high statistical significance with a 0.01

Score Delta: Score remained at 1S

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.

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."

1/1/2015
1S
icon
1S

Score remained at 1S

Description

Syndromic because of causative mutations in Cowden syndrome. Two de novo LGD events in PTEN from recent exome sequencing studies in simplex ASD cases: from O'Roak et al. Nature 2012 (PMID 22495309) a de novo missense variant (p.Thr167Asn) that was ranked severe"; and from O'Roak et al. Science 2012 (PMID 23160955) a de novo frameshift insertion (p.Cys136MetfsX44) was also identified." A de novo LoF variant in the PTEN gene was recently identified in an ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). A detailed examination of ASD cases with heterozygous PTEN mutations found that these cases had a high proportion of missense variants, showed reduced PTEN protein levels, and exhibited prominent white-matter and cognitive abnormalities compared to other groups (PMID 25288137). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified PTEN as a gene meeting high statistical significance with a 0.01

1/1/2016
1S
icon
1S

Score remained at 1S

Description

Syndromic because of causative mutations in Cowden syndrome. Two de novo LoF events in PTEN from recent exome sequencing studies in simplex ASD cases: from O'Roak et al. Nature 2012 (PMID 22495309) a de novo missense variant (p.Thr167Asn) that was ranked severe"; and from O'Roak et al. Science 2012 (PMID 23160955) a de novo frameshift insertion (p.Cys136MetfsX44) was also identified." A de novo LoF variant in the PTEN gene was recently identified in an ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). A detailed examination of ASD cases with heterozygous PTEN mutations found that these cases had a high proportion of missense variants, showed reduced PTEN protein levels, and exhibited prominent white-matter and cognitive abnormalities compared to other groups (PMID 25288137). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified PTEN as a gene meeting high statistical significance with a 0.01

Reports Added
[Novel PTEN germline mutation in a family with mild phenotype: difficulties in genetic counseling.2012] [A recessive form of extreme macrocephaly and mild intellectual disability complements the spectrum of PTEN hamartoma tumour syndrome.2015] [Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders.2011] [Integrated analysis of whole-exome sequencing and transcriptome profiling in males with autism spectrum disorders.2015] [Autism-epilepsy phenotype with macrocephaly suggests PTEN, but not GLIALCAM, genetic screening.2014] [Loss of mTOR repressors Tsc1 or Pten has divergent effects on excitatory and inhibitory synaptic transmission in single hippocampal neuron cultures.2014] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [PTEN mutation in a family with Cowden syndrome and autism.2001] [Biochemical screening and PTEN mutation analysis in individuals with autism spectrum disorders and macrocephaly.2013] [Excess of rare, inherited truncating mutations in autism.2015] [The prevalence of PTEN mutations in a clinical pediatric cohort with autism spectrum disorders, developmental delay, and macrocephaly.2009] [Confirmation study of PTEN mutations among individuals with autism or developmental delays/mental retardation and macrocephaly.2010] [PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer.1997] [The parvalbumin/somatostatin ratio is increased in Pten mutant mice and by human PTEN ASD alleles.2015] [Functionally distinct groups of inherited PTEN mutations in autism and tumour syndromes.2014] [PTEN interacts with histone H1 and controls chromatin condensation.2014] [Electrical signals control wound healing through phosphatidylinositol-3-OH kinase-gamma and PTEN.2006] [Free fatty acids inhibit insulin signaling-stimulated endothelial nitric oxide synthase activation through upregulating PTEN or inhibiting Akt kinase.2006] [Molecular and phenotypic abnormalities in individuals with germline heterozygous PTEN mutations and autism.2014] [Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms.2015] [Autistic spectrum disorder in a 9-year-old girl with macrocephaly.2010] [De novo mutations in epileptic encephalopathies.2013] [Mutation screening of the PTEN gene in patients with autism spectrum disorders and macrocephaly.2007] [Autistic-Like Traits and Cerebellar Dysfunction in Purkinje Cell PTEN Knock-Out Mice.2015] [Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations.2005] [Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.2012] [The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate.1998] [Conformational stability and catalytic activity of PTEN variants linked to cancers and autism spectrum disorders.2015] [A mutant form of PTEN linked to autism.2010] [Novel PTEN mutations in neurodevelopmental disorders and macrocephaly.2008] [A secreted PTEN phosphatase that enters cells to alter signaling and survival.2013] [Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN.1998] [Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.2012] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Neural transcriptome of constitutional Pten dysfunction in mice and its relevance to human idiopathic autism spectrum disorder.2015] [PTEN is recruited to the postsynaptic terminal for NMDA receptor-dependent long-term depression.2010] [Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder.2015] [PTEN knockdown alters dendritic spine/protrusion morphology, not density.2013] [Characteristic brain magnetic resonance imaging pattern in patients with macrocephaly and PTEN mutations.2014]
1/1/2017
1S
icon
1S

Score remained at 1S

Description

Syndromic because of causative mutations in Cowden syndrome. Two de novo LoF events in PTEN from recent exome sequencing studies in simplex ASD cases: from O'Roak et al. Nature 2012 (PMID 22495309) a de novo missense variant (p.Thr167Asn) that was ranked severe"; and from O'Roak et al. Science 2012 (PMID 23160955) a de novo frameshift insertion (p.Cys136MetfsX44) was also identified." A de novo LoF variant in the PTEN gene was recently identified in an ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). A detailed examination of ASD cases with heterozygous PTEN mutations found that these cases had a high proportion of missense variants, showed reduced PTEN protein levels, and exhibited prominent white-matter and cognitive abnormalities compared to other groups (PMID 25288137). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified PTEN as a gene meeting high statistical significance with a 0.01 < FDR ?0.05, meaning that this gene had a ?95% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

10/1/2014
2S
icon
1S

Decreased from 2S to 1S

Description

Syndromic because of causative mutations in Cowden syndrome. Two de novo LGD events in PTEN from recent exome sequencing studies in simplex ASD cases: from O'Roak et al. Nature 2012 (PMID 22495309) a de novo missense variant (p.Thr167Asn) that was ranked severe"; and from O'Roak et al. Science 2012 (PMID 23160955) a de novo frameshift insertion (p.Cys136MetfsX44) was also identified." A de novo LoF variant in the PTEN gene was recently identified in an ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). A detailed examination of ASD cases with heterozygous PTEN mutations found that these cases had a high proportion of missense variants, showed reduced PTEN protein levels, and exhibited prominent white-matter and cognitive abnormalities compared to other groups (PMID 25288137). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified PTEN as a gene meeting high statistical significance with a 0.01

10/1/2015
1S
icon
1S

Decreased from 1S to 1S

Description

Syndromic because of causative mutations in Cowden syndrome. Two de novo LoF events in PTEN from recent exome sequencing studies in simplex ASD cases: from O'Roak et al. Nature 2012 (PMID 22495309) a de novo missense variant (p.Thr167Asn) that was ranked severe"; and from O'Roak et al. Science 2012 (PMID 23160955) a de novo frameshift insertion (p.Cys136MetfsX44) was also identified." A de novo LoF variant in the PTEN gene was recently identified in an ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). A detailed examination of ASD cases with heterozygous PTEN mutations found that these cases had a high proportion of missense variants, showed reduced PTEN protein levels, and exhibited prominent white-matter and cognitive abnormalities compared to other groups (PMID 25288137). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified PTEN as a gene meeting high statistical significance with a 0.01

10/1/2016
1S
icon
1S

Decreased from 1S to 1S

Description

Syndromic because of causative mutations in Cowden syndrome. Two de novo LoF events in PTEN from recent exome sequencing studies in simplex ASD cases: from O'Roak et al. Nature 2012 (PMID 22495309) a de novo missense variant (p.Thr167Asn) that was ranked severe"; and from O'Roak et al. Science 2012 (PMID 23160955) a de novo frameshift insertion (p.Cys136MetfsX44) was also identified." A de novo LoF variant in the PTEN gene was recently identified in an ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). A detailed examination of ASD cases with heterozygous PTEN mutations found that these cases had a high proportion of missense variants, showed reduced PTEN protein levels, and exhibited prominent white-matter and cognitive abnormalities compared to other groups (PMID 25288137). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified PTEN as a gene meeting high statistical significance with a 0.01

10/1/2017
1S
icon
1S

Decreased from 1S to 1S

Description

Variants in PTEN have been identified in individuals presenting with ASD and macrocephaly in multiple studies (PMIDs 15805158, 18759867, 19265751, 20533527). Two de novo deleterious events in the PTEN gene were identified in exome sequencing studies in simplex ASD cases in 2012: a missense variant (p.Thr167Asn) that was classified as "severe" in O'Roak et al. Nature 2012 (PMID 22495309); and a frameshift variant (p.Cys136MetfsX44) in O'Roak et al. Science 2012 (PMID 23160955). A detailed examination of ASD cases with heterozygous PTEN mutations in Frazier et al., 2015 found that these cases had a high proportion of missense variants, showed reduced PTEN protein levels, and exhibited prominent white-matter and cognitive abnormalities compared to other groups (PMID 25288137). An additional de novo loss-of-function variant in the PTEN gene was subsequently identified in an ASD proband from 2,270 trios screened by the Autism Sequencing Consortium in De Rubeis et al., 2014 (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in this report furthermore identified PTEN as a gene meeting high statistical significance with a 0.01 < FDR ? 0.05, meaning that this gene had a ? 95% chance of being a true autism gene. This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). PTEN has also been designated as a syndromic ASD gene, as mutations in the PTEN gene are causative for Cowden syndrome, a disorder in which a subpopulation of individuals with the syndrome develop autism (PMID 11496368).

4/1/2014
No data
icon
2S

Increased from No data to 2S

Description

Syndromic because of causative mutations in Cowden syndrome. Two de novo LGD events in PTEN from recent exome sequencing studies in simplex ASD cases: from O'Roak et al. Nature 2012 (PMID 22495309) a de novo missense variant (p.Thr167Asn) that was ranked severe"; and from O'Roak et al. Science 2012 (PMID 23160955) a de novo frameshift insertion (p.Cys136MetfsX44) was also identified."

4/1/2015
1S
icon
1S

Increased from 1S to 1S

Description

Syndromic because of causative mutations in Cowden syndrome. Two de novo LoF events in PTEN from recent exome sequencing studies in simplex ASD cases: from O'Roak et al. Nature 2012 (PMID 22495309) a de novo missense variant (p.Thr167Asn) that was ranked severe"; and from O'Roak et al. Science 2012 (PMID 23160955) a de novo frameshift insertion (p.Cys136MetfsX44) was also identified." A de novo LoF variant in the PTEN gene was recently identified in an ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). A detailed examination of ASD cases with heterozygous PTEN mutations found that these cases had a high proportion of missense variants, showed reduced PTEN protein levels, and exhibited prominent white-matter and cognitive abnormalities compared to other groups (PMID 25288137). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified PTEN as a gene meeting high statistical significance with a 0.01

4/1/2016
1S
icon
1S

Increased from 1S to 1S

Description

Syndromic because of causative mutations in Cowden syndrome. Two de novo LoF events in PTEN from recent exome sequencing studies in simplex ASD cases: from O'Roak et al. Nature 2012 (PMID 22495309) a de novo missense variant (p.Thr167Asn) that was ranked severe"; and from O'Roak et al. Science 2012 (PMID 23160955) a de novo frameshift insertion (p.Cys136MetfsX44) was also identified." A de novo LoF variant in the PTEN gene was recently identified in an ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). A detailed examination of ASD cases with heterozygous PTEN mutations found that these cases had a high proportion of missense variants, showed reduced PTEN protein levels, and exhibited prominent white-matter and cognitive abnormalities compared to other groups (PMID 25288137). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified PTEN as a gene meeting high statistical significance with a 0.01

Reports Added
[A recessive form of extreme macrocephaly and mild intellectual disability complements the spectrum of PTEN hamartoma tumour syndrome.2015] [Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders.2011] [Integrated analysis of whole-exome sequencing and transcriptome profiling in males with autism spectrum disorders.2015] [Autism-epilepsy phenotype with macrocephaly suggests PTEN, but not GLIALCAM, genetic screening.2014] [Loss of mTOR repressors Tsc1 or Pten has divergent effects on excitatory and inhibitory synaptic transmission in single hippocampal neuron cultures.2014] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Biochemical screening and PTEN mutation analysis in individuals with autism spectrum disorders and macrocephaly.2013] [The prevalence of PTEN mutations in a clinical pediatric cohort with autism spectrum disorders, developmental delay, and macrocephaly.2009] [Novel PTEN mutations in neurodevelopmental disorders and macrocephaly.2008] [PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer.1997] [The parvalbumin/somatostatin ratio is increased in Pten mutant mice and by human PTEN ASD alleles.2015] [Functionally distinct groups of inherited PTEN mutations in autism and tumour syndromes.2014] [PTEN interacts with histone H1 and controls chromatin condensation.2014] [Electrical signals control wound healing through phosphatidylinositol-3-OH kinase-gamma and PTEN.2006] [Free fatty acids inhibit insulin signaling-stimulated endothelial nitric oxide synthase activation through upregulating PTEN or inhibiting Akt kinase.2006] [Molecular and phenotypic abnormalities in individuals with germline heterozygous PTEN mutations and autism.2014] [Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms.2015] [De novo mutations in epileptic encephalopathies.2013] [A Retroviral CRISPR-Cas9 System for Cellular Autism-Associated Phenotype Discovery in Developing Neurons.2016] [PTEN mutation in a family with Cowden syndrome and autism.2001] [Autistic spectrum disorder in a 9-year-old girl with macrocephaly.2010] [Mutation screening of the PTEN gene in patients with autism spectrum disorders and macrocephaly.2007] [Autistic-Like Traits and Cerebellar Dysfunction in Purkinje Cell PTEN Knock-Out Mice.2015] [Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations.2005] [Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.2012] [The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate.1998] [Confirmation study of PTEN mutations among individuals with autism or developmental delays/mental retardation and macrocephaly.2010] [Conformational stability and catalytic activity of PTEN variants linked to cancers and autism spectrum disorders.2015] [A mutant form of PTEN linked to autism.2010] [A secreted PTEN phosphatase that enters cells to alter signaling and survival.2013] [Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN.1998] [Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.2012] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Neural transcriptome of constitutional Pten dysfunction in mice and its relevance to human idiopathic autism spectrum disorder.2015] [PTEN is recruited to the postsynaptic terminal for NMDA receptor-dependent long-term depression.2010] [Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder.2015] [Excess of rare, inherited truncating mutations in autism.2015] [PTEN knockdown alters dendritic spine/protrusion morphology, not density.2013] [Characteristic brain magnetic resonance imaging pattern in patients with macrocephaly and PTEN mutations.2014] [Novel PTEN germline mutation in a family with mild phenotype: difficulties in genetic counseling.2012]
4/1/2017
1S
icon
1S

Increased from 1S to 1S

Description

Syndromic because of causative mutations in Cowden syndrome. Two de novo LoF events in PTEN from recent exome sequencing studies in simplex ASD cases: from O'Roak et al. Nature 2012 (PMID 22495309) a de novo missense variant (p.Thr167Asn) that was ranked severe"; and from O'Roak et al. Science 2012 (PMID 23160955) a de novo frameshift insertion (p.Cys136MetfsX44) was also identified." A de novo LoF variant in the PTEN gene was recently identified in an ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). A detailed examination of ASD cases with heterozygous PTEN mutations found that these cases had a high proportion of missense variants, showed reduced PTEN protein levels, and exhibited prominent white-matter and cognitive abnormalities compared to other groups (PMID 25288137). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified PTEN as a gene meeting high statistical significance with a 0.01< FDR ?0.05, meaning that this gene had a ?95% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

Reports Added
[Characteristic brain magnetic resonance imaging pattern in patients with macrocephaly and PTEN mutations.2014] [Novel PTEN germline mutation in a family with mild phenotype: difficulties in genetic counseling.2012] [Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders.2011] [Autism-epilepsy phenotype with macrocephaly suggests PTEN, but not GLIALCAM, genetic screening.2014] [Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder.2017] [Loss of mTOR repressors Tsc1 or Pten has divergent effects on excitatory and inhibitory synaptic transmission in single hippocampal neuron cultures.2014] [Biochemical screening and PTEN mutation analysis in individuals with autism spectrum disorders and macrocephaly.2013] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Integrated analysis of whole-exome sequencing and transcriptome profiling in males with autism spectrum disorders.2015] [A recessive form of extreme macrocephaly and mild intellectual disability complements the spectrum of PTEN hamartoma tumour syndrome.2015] [The prevalence of PTEN mutations in a clinical pediatric cohort with autism spectrum disorders, developmental delay, and macrocephaly.2009] [Novel PTEN mutations in neurodevelopmental disorders and macrocephaly.2008] [PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer.1997] [The parvalbumin/somatostatin ratio is increased in Pten mutant mice and by human PTEN ASD alleles.2015] [Functionally distinct groups of inherited PTEN mutations in autism and tumour syndromes.2014] [PTEN interacts with histone H1 and controls chromatin condensation.2014] [De novo mutations in epileptic encephalopathies.2013] [Electrical signals control wound healing through phosphatidylinositol-3-OH kinase-gamma and PTEN.2006] [Free fatty acids inhibit insulin signaling-stimulated endothelial nitric oxide synthase activation through upregulating PTEN or inhibiting Akt kinase.2006] [Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.2012] [Molecular and phenotypic abnormalities in individuals with germline heterozygous PTEN mutations and autism.2014] [Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms.2015] [PTEN mutation in a family with Cowden syndrome and autism.2001] [Autistic spectrum disorder in a 9-year-old girl with macrocephaly.2010] [A Retroviral CRISPR-Cas9 System for Cellular Autism-Associated Phenotype Discovery in Developing Neurons.2016] [Mutation screening of the PTEN gene in patients with autism spectrum disorders and macrocephaly.2007] [Excess of rare, inherited truncating mutations in autism.2015] [Autistic-Like Traits and Cerebellar Dysfunction in Purkinje Cell PTEN Knock-Out Mice.2015] [Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations.2005] [Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.2012] [The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate.1998] [Confirmation study of PTEN mutations among individuals with autism or developmental delays/mental retardation and macrocephaly.2010] [A combination of genetic and biochemical analyses for the diagnosis of PI3K-AKT-mTOR pathway-associated megalencephaly.2017] [Conformational stability and catalytic activity of PTEN variants linked to cancers and autism spectrum disorders.2015] [A mutant form of PTEN linked to autism.2010] [A secreted PTEN phosphatase that enters cells to alter signaling and survival.2013] [Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN.1998] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Neural transcriptome of constitutional Pten dysfunction in mice and its relevance to human idiopathic autism spectrum disorder.2015] [PTEN is recruited to the postsynaptic terminal for NMDA receptor-dependent long-term depression.2010] [Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder.2015] [Prevalence of four Mendelian disorders associated with autism in 2392 affected families.2017] [PTEN knockdown alters dendritic spine/protrusion morphology, not density.2013]
7/1/2014
No data
icon
2S

Increased from No data to 2S

Description

Syndromic because of causative mutations in Cowden syndrome. Two de novo LGD events in PTEN from recent exome sequencing studies in simplex ASD cases: from O'Roak et al. Nature 2012 (PMID 22495309) a de novo missense variant (p.Thr167Asn) that was ranked severe"; and from O'Roak et al. Science 2012 (PMID 23160955) a de novo frameshift insertion (p.Cys136MetfsX44) was also identified."

Reports Added
[PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer.1997] [The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate.1998] [Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN.1998] [PTEN mutation in a family with Cowden syndrome and autism.2001] [Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations.2005] [Electrical signals control wound healing through phosphatidylinositol-3-OH kinase-gamma and PTEN.2006] [Free fatty acids inhibit insulin signaling-stimulated endothelial nitric oxide synthase activation through upregulating PTEN or inhibiting Akt kinase.2006] [Mutation screening of the PTEN gene in patients with autism spectrum disorders and macrocephaly.2007] [PTEN is recruited to the postsynaptic terminal for NMDA receptor-dependent long-term depression.2010] [Autistic spectrum disorder in a 9-year-old girl with macrocephaly.2010] [Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders.2011] [Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.2012] [Novel PTEN germline mutation in a family with mild phenotype: difficulties in genetic counseling.2012] [Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.2012] [Biochemical screening and PTEN mutation analysis in individuals with autism spectrum disorders and macrocephaly.2013] [A secreted PTEN phosphatase that enters cells to alter signaling and survival.2013] [De novo mutations in epileptic encephalopathies.2013] [PTEN knockdown alters dendritic spine/protrusion morphology, not density.2013] [Characteristic brain magnetic resonance imaging pattern in patients with macrocephaly and PTEN mutations.2014] [Loss of mTOR repressors Tsc1 or Pten has divergent effects on excitatory and inhibitory synaptic transmission in single hippocampal neuron cultures.2014] [Autism-epilepsy phenotype with macrocephaly suggests PTEN, but not GLIALCAM, genetic screening.2014] [PTEN interacts with histone H1 and controls chromatin condensation.2014]
7/1/2015
1S
icon
1S

Increased from 1S to 1S

Description

Syndromic because of causative mutations in Cowden syndrome. Two de novo LoF events in PTEN from recent exome sequencing studies in simplex ASD cases: from O'Roak et al. Nature 2012 (PMID 22495309) a de novo missense variant (p.Thr167Asn) that was ranked severe"; and from O'Roak et al. Science 2012 (PMID 23160955) a de novo frameshift insertion (p.Cys136MetfsX44) was also identified." A de novo LoF variant in the PTEN gene was recently identified in an ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). A detailed examination of ASD cases with heterozygous PTEN mutations found that these cases had a high proportion of missense variants, showed reduced PTEN protein levels, and exhibited prominent white-matter and cognitive abnormalities compared to other groups (PMID 25288137). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified PTEN as a gene meeting high statistical significance with a 0.01

Reports Added
[Characteristic brain magnetic resonance imaging pattern in patients with macrocephaly and PTEN mutations.2014] [Novel PTEN germline mutation in a family with mild phenotype: difficulties in genetic counseling.2012] [Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders.2011] [Integrated analysis of whole-exome sequencing and transcriptome profiling in males with autism spectrum disorders.2015] [Autism-epilepsy phenotype with macrocephaly suggests PTEN, but not GLIALCAM, genetic screening.2014] [Loss of mTOR repressors Tsc1 or Pten has divergent effects on excitatory and inhibitory synaptic transmission in single hippocampal neuron cultures.2014] [Biochemical screening and PTEN mutation analysis in individuals with autism spectrum disorders and macrocephaly.2013] [The prevalence of PTEN mutations in a clinical pediatric cohort with autism spectrum disorders, developmental delay, and macrocephaly.2009] [Confirmation study of PTEN mutations among individuals with autism or developmental delays/mental retardation and macrocephaly.2010] [PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer.1997] [The parvalbumin/somatostatin ratio is increased in Pten mutant mice and by human PTEN ASD alleles.2015] [Functionally distinct groups of inherited PTEN mutations in autism and tumour syndromes.2014] [PTEN interacts with histone H1 and controls chromatin condensation.2014] [Electrical signals control wound healing through phosphatidylinositol-3-OH kinase-gamma and PTEN.2006] [Free fatty acids inhibit insulin signaling-stimulated endothelial nitric oxide synthase activation through upregulating PTEN or inhibiting Akt kinase.2006] [Molecular and phenotypic abnormalities in individuals with germline heterozygous PTEN mutations and autism.2014] [Autistic spectrum disorder in a 9-year-old girl with macrocephaly.2010] [PTEN mutation in a family with Cowden syndrome and autism.2001] [Mutation screening of the PTEN gene in patients with autism spectrum disorders and macrocephaly.2007] [De novo mutations in epileptic encephalopathies.2013] [Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations.2005] [Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.2012] [The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate.1998] [Conformational stability and catalytic activity of PTEN variants linked to cancers and autism spectrum disorders.2015] [A mutant form of PTEN linked to autism.2010] [A secreted PTEN phosphatase that enters cells to alter signaling and survival.2013] [Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN.1998] [Novel PTEN mutations in neurodevelopmental disorders and macrocephaly.2008] [Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.2012] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Neural transcriptome of constitutional Pten dysfunction in mice and its relevance to human idiopathic autism spectrum disorder.2015] [PTEN is recruited to the postsynaptic terminal for NMDA receptor-dependent long-term depression.2010] [Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder.2015] [Excess of rare, inherited truncating mutations in autism.2015] [PTEN knockdown alters dendritic spine/protrusion morphology, not density.2013]
7/1/2016
1S
icon
1S

Increased from 1S to 1S

Description

Syndromic because of causative mutations in Cowden syndrome. Two de novo LoF events in PTEN from recent exome sequencing studies in simplex ASD cases: from O'Roak et al. Nature 2012 (PMID 22495309) a de novo missense variant (p.Thr167Asn) that was ranked severe"; and from O'Roak et al. Science 2012 (PMID 23160955) a de novo frameshift insertion (p.Cys136MetfsX44) was also identified." A de novo LoF variant in the PTEN gene was recently identified in an ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). A detailed examination of ASD cases with heterozygous PTEN mutations found that these cases had a high proportion of missense variants, showed reduced PTEN protein levels, and exhibited prominent white-matter and cognitive abnormalities compared to other groups (PMID 25288137). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified PTEN as a gene meeting high statistical significance with a 0.01

7/1/2017
1S
icon
1S

Increased from 1S to 1S

Description

Variants in PTEN have been identified in individuals presenting with ASD and macrocephaly in multiple studies (PMIDs 15805158, 18759867, 19265751, 20533527). Two de novo deleterious events in the PTEN gene were identified in exome sequencing studies in simplex ASD cases in 2012: a missense variant (p.Thr167Asn) that was classified as "severe" in O'Roak et al. Nature 2012 (PMID 22495309); and a frameshift variant (p.Cys136MetfsX44) in O'Roak et al. Science 2012 (PMID 23160955). A detailed examination of ASD cases with heterozygous PTEN mutations in Frazier et al., 2015 found that these cases had a high proportion of missense variants, showed reduced PTEN protein levels, and exhibited prominent white-matter and cognitive abnormalities compared to other groups (PMID 25288137). An additional de novo loss-of-function variant in the PTEN gene was subsequently identified in an ASD proband from 2,270 trios screened by the Autism Sequencing Consortium in De Rubeis et al., 2014 (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in this report furthermore identified PTEN as a gene meeting high statistical significance with a 0.01 < FDR ? 0.05, meaning that this gene had a ? 95% chance of being a true autism gene. This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). PTEN has also been designated as a syndromic ASD gene, as mutations in the PTEN gene are causative for Cowden syndrome, a disorder in which a subpopulation of individuals with the syndrome develop autism (PMID 11496368).

Krishnan Probability Score

Score 0.49831091848158

Ranking 2260/25841 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 0.97550686584803

Ranking 2246/18225 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
Iossifov Probability Score

Score 0.973

Ranking 52/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Sanders TADA Score

Score 0.00071064664987682

Ranking 18/18665 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 82

Ranking 13/461 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 0.24988226958981

Ranking 3481/20870 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.
CNVs associated with PTEN(1 CNVs)
10q23.31 7 Deletion 13  /  42
Animal Models associated with PTEN(21 Models)
PTEN_10_CKO_HM Genetic
PTEN_10_CKO_HT Genetic
PTEN_11_CKO_HM Genetic
PTEN_11_CKO_HT Genetic
PTEN_12_CKO_HM Genetic
PTEN_12_CKO_HT Genetic
PTEN_17_CKO_HM Genetic
PTEN_18_CKO_HT_Seizure_IN Genetic
PTEN_19_KO_HM Genetic
PTEN_1_CKO_HM Genetic
PTEN_1_CKO_HM_Rapamycin-1 RESCUE-Pharmaceutical
PTEN_1_CKO_HM_Rapamycin-2 RESCUE-Pharmaceutical
PTEN_2_CKO_HT Genetic
PTEN_3_CKO_HM Genetic
PTEN_4_KI_ M3M4_HM Genetic
PTEN_5_KI_M3M4_HT Genetic
PTEN_6_KO_HT Genetic
PTEN_7_CKO_HM Genetic
PTEN_8_CKO_HM Genetic
PTEN_9_CKO_HM Genetic
PTEN_9_CKO_HT Genetic
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
Beclin-1 Beclin-1 Human Direct Regulation 8678 Q14457
BMP9 Growth/differentiation factor 2 Mouse Protein Binding 12165 Q9WV56
C19orf29OS chromosome 19 open reading frame 29 opposite strand Human Protein Binding 404665 Q8N1I8
CHGB chromogranin B (secretogranin 1) Human Protein Binding 1114 P05060
cyclin D1 G1/S-specific cyclin-D1 Human Protein Binding 595 P24385
DJ1 Protein deglycase DJ-1 Human Protein Modification 11315 Q99497
FRK fyn-related kinase Human Protein Modification 2444 P42685
GFRA2 GDNF family receptor alpha 2 Human Protein Binding 2675 E9PD47
GPR113 G protein-coupled receptor 113 Human Protein Binding 165082 Q8IZF5
HBA1 hemoglobin, alpha 1 Human Protein Binding 3039 P69905
Histone H1.2 Histone H1.2 Human Protein Binding 3006 P16403
HP1 alpha Chromobox protein homolog 5 Human Protein Binding 23468 P45973
LEPREL4 leprecan-like 4 Human Protein Binding 10609 Q92791
lncRNA-BGL3 beta globin locus transcript 3 (non-protein coding) Human RNA Binding 103344929 N/A
miR-106b microRNA 106b Human RNA Binding 406900 N/A
miR-130b microRNA 130b Human RNA Binding 406920 N/A
miR-21 microRNA 21 Human RNA Binding 406991 N/A
miR-221 microRNA 221 Human RNA Binding 407006
miR-29a microRNA mir-29a Rat RNA Binding 100314230 N/A
miR-518c microRNA 518c Human RNA Binding 574477 N/A
miR-638 microRNA 638 Human RNA Binding 693223 N/A
miR-7 leukocyte immunoglobulin-like receptor, subfamily B (with TM and ITIM domains), member 1 Human RNA Binding 10859 Q8NHL6
miR-802 microRNA 802 Human RNA Binding 768219 N/A
miR-92a microRNA 29a Human Direct Regulation 407021 N/A
miR-BART7 ebv-mir-BART7 (MI0003729) HHV-4 RNA Binding N/A N/A
miR1297 microRNA 1297 Human RNA Binding 100302187 N/A
miR20b microRNA 20b Human RNA Binding 574032 N/A
miR214 microRNA 214 Human RNA Binding 406996 N/A
MIR221 microRNA 221 Human RNA Binding 407006 N/A
miR26a microRNA 26a-1 Human RNA Binding 407015 N/A
MIR29C microRNA 29c Human RNA Binding 407026 N/A
p21 cyclin-dependent kinase inhibitor 1A (p21, Cip1) Human Protein Binding 1026 P38936
PTPN6 protein tyrosine phosphatase, non-receptor type 6 Human Protein Modification 5777 P29350
PTPRZ1 N/A Pig Protein Modification 100511294 N/A
QRFPR pyroglutamylated RFamide peptide receptor Human Protein Binding 84109 Q96P65
SLUG Zinc finger protein SNAI2 Human DNA Binding 6591 O43623
TCEB3C transcription elongation factor B polypeptide 3C (elongin A3) Human Protein Binding 162699 Q8NG57
TNKS1 Tankyrase-1 Human Protein Modification 8658 O95271
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