Human Gene Module / Chromosome 1 / MTOR

MTORMechanistic target of rapamycin (serine/threonine kinase)

Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
7 / 18
Rare Variants / Common Variants
26 / 0
Aliases
MTOR, FRAP,  FRAP1,  FRAP2,  RAFT1,  RAPT1
Associated Syndromes
Smith-Kingsmore syndrome
Genetic Category
Rare Single Gene Mutation, Syndromic, Functional
Chromosome Band
1p36.22
Associated Disorders
ASD, EP, EPS
Relevance to Autism

A previously observed gain-of-function missense variant in the MTOR gene (c.5395G>A; p.Glu1799Lys) that likely arose through gonadal mosaicism was identified in two affected brothers, aged 6 and 23 years, who presented with ASD, intellectual disability, macrocephaly (+5 SD), and megalencephaly (Mroske et al., 2015).

Molecular Function

This gene encodes a serine/threonine protein kinase which is a central regulator of cellular metabolism, growth and survival in response to hormones, growth factors, nutrients, energy and stress signals. MTOR directly or indirectly regulates the phosphorylation of at least 800 proteins.

Reports related to MTOR (18 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly. Lee JH , et al. (2012) No -
2 Support De novo mutations in epileptic encephalopathies. Epi4K Consortium , et al. (2013) No -
3 Support The contribution of de novo coding mutations to autism spectrum disorder. Iossifov I , et al. (2014) Yes -
4 Support Decreased mTOR signaling pathway in human idiopathic autism and in rats exposed to valproic acid. Nicolini C , et al. (2015) Yes -
5 Support Imbalanced mechanistic target of rapamycin C1 and C2 activity in the cerebellum of Angelman syndrome mice impairs motor function. Sun J , et al. (2015) No -
6 Support A germline MTOR mutation in Aboriginal Australian siblings with intellectual disability, dysmorphism, macrocephaly, and small thoraces. Baynam G , et al. (2015) No Megalencephaly
7 Primary Germline activating MTOR mutation arising through gonadal mosaicism in two brothers with megalencephaly and neurodevelopmental abnormalities. Mroske C , et al. (2015) Yes Macrocephaly, megalencephaly
8 Recent Recommendation Association of MTOR Mutations With Developmental Brain Disorders, Including Megalencephaly, Focal Cortical Dysplasia, and Pigmentary Mosaicism. Mirzaa GM , et al. (2016) No Epilepsy/seizures, ASD
9 Support Candidate-gene criteria for clinical reporting: diagnostic exome sequencing identifies altered candidate genes among 8% of patients with undiagnose... Farwell Hagman KD , et al. (2016) No -
10 Support Pathologic Active mTOR Mutation in Brain Malformation with Intractable Epilepsy Leads to Cell-Autonomous Migration Delay. Hanai S , et al. (2017) No Hemimegalencephaly, focal cortical dysplasia
11 Support Genomic diagnosis for children with intellectual disability and/or developmental delay. Bowling KM , et al. (2017) Yes -
12 Support mTOR mutations in Smith-Kingsmore syndrome: Four additional patients and a review. Gordo G , et al. (2017) No ASD
13 Support Variation in a range of mTOR-related genes associates with intracranial volume and intellectual disability. Reijnders MRF , et al. (2017) No Macrocephaly
14 Support Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder. Takata A , et al. (2018) Yes -
15 Recent Recommendation Brain Somatic Mutations in MTOR Disrupt Neuronal Ciliogenesis, Leading to Focal Cortical Dyslamination. Park SM , et al. (2018) No -
16 Support Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population. Monies D , et al. (2019) Yes -
17 Support Increased diagnostic and new genes identification outcome using research reanalysis of singleton exome sequencing. Bruel AL , et al. (2019) No -
18 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks. Ruzzo EK , et al. (2019) Yes -
Rare Variants   (26)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.4376C>A p.Ala1459Asp missense_variant - - - 28427592 Hanai S , et al. (2017)
c.4448G>A p.Cys1483Tyr missense_variant Unknown - - 28892148 Gordo G , et al. (2017)
c.6605T>G p.Phe2202Cys missense_variant Unknown - - 28892148 Gordo G , et al. (2017)
c.4448G>A p.Cys1483Tyr missense_variant De novo NA - 22729223 Lee JH , et al. (2012)
c.5395G>A p.Glu1799Lys missense_variant De novo NA - 28892148 Gordo G , et al. (2017)
c.4379T>C p.Leu1460Pro missense_variant Unknown - - 27159400 Mirzaa GM , et al. (2016)
c.5809C>T p.Gln1937Ter missense_variant Unknown - - 27159400 Mirzaa GM , et al. (2016)
c.5930C>T p.Thr1977Ile missense_variant Unknown - - 27159400 Mirzaa GM , et al. (2016)
c.6644C>A p.Ser2215Tyr missense_variant Unknown - - 27159400 Mirzaa GM , et al. (2016)
c.6644C>T p.Ser2215Phe missense_variant Unknown - - 27159400 Mirzaa GM , et al. (2016)
c.5395G>A p.Glu1799Lys missense_variant De novo NA - 27159400 Mirzaa GM , et al. (2016)
c.505-2A>G - splice_site_variant Unknown - Multiplex 28554332 Bowling KM , et al. (2017)
c.4785G>A p.Met1595Ile missense_variant De novo NA - 28554332 Bowling KM , et al. (2017)
c.5663T>G p.Phe1888Cys missense_variant De novo NA - 28554332 Bowling KM , et al. (2017)
c.6981G>A p.Met2327Ile missense_variant De novo NA - 28554332 Bowling KM , et al. (2017)
c.617G>A p.Arg206His missense_variant De novo NA Simplex 29346770 Takata A , et al. (2018)
c.4555G>A p.Ala1519Thr missense_variant De novo NA - 29051493 Reijnders MRF , et al. (2017)
c.2403A>G p.Thr801%3D splice_site_variant Unknown - Unknown 31130284 Monies D , et al. (2019)
c.4306_4307delinsTT p.Ala1436Phe missense_variant Unknown - - 31231135 Bruel AL , et al. (2019)
c.5395G>A p.Glu1799Lys missense_variant De novo NA Multiplex 25851998 Baynam G , et al. (2015)
c.6158C>T p.Pro2053Leu missense_variant De novo NA Multiplex 31398340 Ruzzo EK , et al. (2019)
c.4732A>G p.Met1578Val missense_variant De novo NA Simplex 25363768 Iossifov I , et al. (2014)
c.5395G>A p.Glu1799Lys missense_variant De novo NA - 27513193 Farwell Hagman KD , et al. (2016)
c.4785G>A p.Met1595Ile missense_variant De novo NA Simplex 23934111 Epi4K Consortium , et al. (2013)
c.5395G>A p.Glu1799Lys missense_variant De novo NA Multiplex (monozygotic twins) 27159400 Mirzaa GM , et al. (2016)
c.5395G>A p.Glu1799Lys missense_variant Unknown (likely gonadal mosaicism) - Multiplex 26542245 Mroske C , et al. (2015)
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, Syndromic

A previously observed gain-of-function missense variant in the MTOR gene (c.5395G>A; p.Glu1799Lys) that likely arose through gonadal mosaicism was identified in two affected brothers, aged 6 and 23 years, who presented with ASD, intellectual disability, macrocephaly (+5 SD), and megalencephaly (Mroske et al., 2015). Sequencing of patients with focal cortical dysplasia, hemimegalencephaly, and diffuse megalencephaly in Mirzaa et al., 2016 identified the p.Glu1799Lys missense variant as a constitutional de novo variant in identical twin brothers with autism at 17 years of age, seizures, and diffuse megalencephaly; functional analysis of this variant in electroporated rat neurons demonstrated constitutive activation following starvation (as measured by S6 immunofluoroscence) and increased neuronal cell size.. Mutations in the MTOR gene are also associated with Smith-Kingsmore syndrome (SKS, OMIM 616638), a syndromic from of intellectual disability characterized by macrocephaly, seizures, umbilical hernia, and facial dysmorphic features (Lee et al., 2012; Baynam et al., 2015). Mosaic MTOR variants have also been identified in patients presenting with focal cortical dysplasia and megalencephaly (Mirzaa et al., 2016). Gordo et al., 2018 identified 4 new cases of Smith-Kingsmore syndrome, reviewed the phenotypic profiles of 23 patients previously described in the literature, and reported that autistic spectrum disorder was a clinical finding in 8/27 SKS cases (29.6%).

Score Delta: Decreased from 3S to 2S

2

Strong Candidate

See all Category 2 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."

10/1/2019
3S
icon
2S

Decreased from 3S to 2S

New Scoring Scheme
Description

A previously observed gain-of-function missense variant in the MTOR gene (c.5395G>A; p.Glu1799Lys) that likely arose through gonadal mosaicism was identified in two affected brothers, aged 6 and 23 years, who presented with ASD, intellectual disability, macrocephaly (+5 SD), and megalencephaly (Mroske et al., 2015). Sequencing of patients with focal cortical dysplasia, hemimegalencephaly, and diffuse megalencephaly in Mirzaa et al., 2016 identified the p.Glu1799Lys missense variant as a constitutional de novo variant in identical twin brothers with autism at 17 years of age, seizures, and diffuse megalencephaly; functional analysis of this variant in electroporated rat neurons demonstrated constitutive activation following starvation (as measured by S6 immunofluoroscence) and increased neuronal cell size.. Mutations in the MTOR gene are also associated with Smith-Kingsmore syndrome (SKS, OMIM 616638), a syndromic from of intellectual disability characterized by macrocephaly, seizures, umbilical hernia, and facial dysmorphic features (Lee et al., 2012; Baynam et al., 2015). Mosaic MTOR variants have also been identified in patients presenting with focal cortical dysplasia and megalencephaly (Mirzaa et al., 2016). Gordo et al., 2018 identified 4 new cases of Smith-Kingsmore syndrome, reviewed the phenotypic profiles of 23 patients previously described in the literature, and reported that autistic spectrum disorder was a clinical finding in 8/27 SKS cases (29.6%).

Reports Added
[New Scoring Scheme]
7/1/2019
3S
icon
3S

Decreased from 3S to 3S

Description

A previously observed gain-of-function missense variant in the MTOR gene (c.5395G>A; p.Glu1799Lys) that likely arose through gonadal mosaicism was identified in two affected brothers, aged 6 and 23 years, who presented with ASD, intellectual disability, macrocephaly (+5 SD), and megalencephaly (Mroske et al., 2015). Sequencing of patients with focal cortical dysplasia, hemimegalencephaly, and diffuse megalencephaly in Mirzaa et al., 2016 identified the p.Glu1799Lys missense variant as a constitutional de novo variant in identical twin brothers with autism at 17 years of age, seizures, and diffuse megalencephaly; functional analysis of this variant in electroporated rat neurons demonstrated constitutive activation following starvation (as measured by S6 immunofluoroscence) and increased neuronal cell size.. Mutations in the MTOR gene are also associated with Smith-Kingsmore syndrome (SKS, OMIM 616638), a syndromic from of intellectual disability characterized by macrocephaly, seizures, umbilical hernia, and facial dysmorphic features (Lee et al., 2012; Baynam et al., 2015). Mosaic MTOR variants have also been identified in patients presenting with focal cortical dysplasia and megalencephaly (Mirzaa et al., 2016). Gordo et al., 2018 identified 4 new cases of Smith-Kingsmore syndrome, reviewed the phenotypic profiles of 23 patients previously described in the literature, and reported that autistic spectrum disorder was a clinical finding in 8/27 SKS cases (29.6%).

7/1/2018
4.5 + acc2 + S
icon
3S

Decreased from 4.5 + acc2 + S to 3S

Description

A previously observed gain-of-function missense variant in the MTOR gene (c.5395G>A; p.Glu1799Lys) that likely arose through gonadal mosaicism was identified in two affected brothers, aged 6 and 23 years, who presented with ASD, intellectual disability, macrocephaly (+5 SD), and megalencephaly (Mroske et al., 2015). Sequencing of patients with focal cortical dysplasia, hemimegalencephaly, and diffuse megalencephaly in Mirzaa et al., 2016 identified the p.Glu1799Lys missense variant as a constitutional de novo variant in identical twin brothers with autism at 17 years of age, seizures, and diffuse megalencephaly; functional analysis of this variant in electroporated rat neurons demonstrated constitutive activation following starvation (as measured by S6 immunofluoroscence) and increased neuronal cell size.. Mutations in the MTOR gene are also associated with Smith-Kingsmore syndrome (SKS, OMIM 616638), a syndromic from of intellectual disability characterized by macrocephaly, seizures, umbilical hernia, and facial dysmorphic features (Lee et al., 2012; Baynam et al., 2015). Mosaic MTOR variants have also been identified in patients presenting with focal cortical dysplasia and megalencephaly (Mirzaa et al., 2016). Gordo et al., 2018 identified 4 new cases of Smith-Kingsmore syndrome, reviewed the phenotypic profiles of 23 patients previously described in the literature, and reported that autistic spectrum disorder was a clinical finding in 8/27 SKS cases (29.6%).

10/1/2017
3
icon
3

Increased from 3 to 3

Description

A previously observed gain-of-function missense variant in the MTOR gene (c.5395G>A; p.Glu1799Lys) that likely arose through gonadal mosaicism was identified in two affected brothers, aged 6 and 23 years, who presented with ASD, intellectual disability, macrocephaly (+5 SD), and megalencephaly (Mroske et al., 2015). Sequencing of patients with focal cortical dysplasia, hemimegalencephaly, and diffuse megalencephaly in Mirzaa et al., 2016 identified the p.Glu1799Lys missense variant as a constitutional de novo variant in identical twin brothers with autism at 17 years of age, seizures, and diffuse megalencephaly; functional analysis of this variant in electroporated rat neurons demonstrated constitutive activation following starvation (as measured by S6 immunofluoroscence) and increased neuronal cell size.. Mutations in the MTOR gene are also associated with Smith-Kingsmore syndrome (SKS, OMIM 616638), a syndromic from of intellectual disability characterized by macrocephaly, seizures, umbilical hernia, and facial dysmorphic features (Lee et al., 2012; Baynam et al., 2015). Mosaic MTOR variants have also been identified in patients presenting with focal cortical dysplasia and megalencephaly (Mirzaa et al., 2016).

4/1/2017
3
icon
3

Increased from 3 to 3

Description

A previously observed gain-of-function missense variant in the MTOR gene (c.5395G>A; p.Glu1799Lys) that likely arose through gonadal mosaicism was identified in two affected brothers, aged 6 and 23 years, who presented with ASD, intellectual disability, macrocephaly (+5 SD), and megalencephaly (Mroske et al., 2015). Sequencing of patients with focal cortical dysplasia, hemimegalencephaly, and diffuse megalencephaly in Mirzaa et al., 2016 identified the p.Glu1799Lys missense variant as a constitutional de novo variant in identical twin brothers with autism at 17 years of age, seizures, and diffuse megalencephaly; functional analysis of this variant in electroporated rat neurons demonstrated constitutive activation following starvation (as measured by S6 immunofluoroscence) and increased neuronal cell size.. Mutations in the MTOR gene are also associated with Smith-Kingsmore syndrome (SKS, OMIM 616638), a syndromic from of intellectual disability characterized by macrocephaly, seizures, umbilical hernia, and facial dysmorphic features (Lee et al., 2012; Baynam et al., 2015). Mosaic MTOR variants have also been identified in patients presenting with focal cortical dysplasia and megalencephaly (Mirzaa et al., 2016).

7/1/2016
3
icon
3

Increased from 3 to 3

Description

A previously observed gain-of-function missense variant in the MTOR gene (c.5395G>A; p.Glu1799Lys) that likely arose through gonadal mosaicism was identified in two affected brothers, aged 6 and 23 years, who presented with ASD, intellectual disability, macrocephaly (+5 SD), and megalencephaly (Mroske et al., 2015). Sequencing of patients with focal cortical dysplasia, hemimegalencephaly, and diffuse megalencephaly in Mirzaa et al., 2016 identified the p.Glu1799Lys missense variant as a constitutional de novo variant in identical twin brothers with autism at 17 years of age, seizures, and diffuse megalencephaly; functional analysis of this variant in electroporated rat neurons demonstrated constitutive activation following starvation (as measured by S6 immunofluoroscence) and increased neuronal cell size.. Mutations in the MTOR gene are also associated with Smith-Kingsmore syndrome (SKS, OMIM 616638), a syndromic from of intellectual disability characterized by macrocephaly, seizures, umbilical hernia, and facial dysmorphic features (Lee et al., 2012; Baynam et al., 2015). Mosaic MTOR variants have also been identified in patients presenting with focal cortical dysplasia and megalencephaly (Mirzaa et al., 2016).

4/1/2016
3
icon
3

Increased from 3 to 3

Description

A previously observed gain-of-function missense variant in the MTOR gene (c.5395G>A; p.Glu1799Lys) that likely arose through gonadal mosaicism was identified in two affected brothers, aged 6 and 23 years, who presented with ASD, intellectual disability, macrocephaly (+5 SD), and megalencephaly (Mroske et al., 2015). Sequencing of patients with focal cortical dysplasia, hemimegalencephaly, and diffuse megalencephaly in Mirzaa et al., 2016 identified the p.Glu1799Lys missense variant as a constitutional de novo variant in identical twin brothers with autism at 17 years of age, seizures, and diffuse megalencephaly; functional analysis of this variant in electroporated rat neurons demonstrated constitutive activation following starvation (as measured by S6 immunofluoroscence) and increased neuronal cell size.. Mutations in the MTOR gene are also associated with Smith-Kingsmore syndrome (SKS, OMIM 616638), a syndromic from of intellectual disability characterized by macrocephaly, seizures, umbilical hernia, and facial dysmorphic features (Lee et al., 2012; Baynam et al., 2015). Mosaic MTOR variants have also been identified in patients presenting with focal cortical dysplasia and megalencephaly (Mirzaa et al., 2016).

10/1/2015
icon
3

Increased from to 3

Description

A previously observed gain-of-function missense variant in the MTOR gene (c.5395G>A; p.Glu1799Lys) that likely arose through gonadal mosaicism was identified in two affected brothers, aged 6 and 23 years, who presented with ASD, intellectual disability, macrocephaly (+5 SD), and megalencephaly (Mroske et al., 2015). Mutations in the MTOR gene are also associated with Smith-Kingsmore syndrome (SKS, OMIM 616638), a syndromic from of intellectual disability characterized by macrocephaly, seizures, umbilical hernia, and facial dysmorphic features (Lee et al., 2012; Baynam et al., 2015).

Krishnan Probability Score

Score 0.44536669500627

Ranking 15435/25841 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 0.99999999999968

Ranking 36/18225 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 0.93443341162771

Ranking 12567/18665 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 0.33563613524664

Ranking 2202/20870 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
DPEP1 Dipeptidase 1 Human Protein Binding 1800 P16444
LYPD3 Ly6/PLAUR domain-containing protein 3 Human Protein Binding 27076 O95274
NT5E 5'-nucleotidase Human Protein Binding 4907 P21589
PONTIN regulatory associated protein of mTOR Human Protein Binding 53439 Q9VH07
REPTIN regulatory associated protein of mTOR Human Protein Binding 40092 Q9V3K3
TEL2 regulatory associated protein of mTOR Human Protein Binding 9894 Q9Y4R8
VIPR2 vasoactive intestinal peptide receptor 2 Human Protein Binding 7434 P41587
VSIG2 V-set and immunoglobulin domain containing 2 Human Protein Binding 23584 Q96IQ7
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