Human Gene Module / Chromosome 1 / MTOR

MTORmechanistic target of rapamycin kinase

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
15 / 35
Rare Variants / Common Variants
58 / 0
Aliases
MTOR, FRAP,  FRAP1,  FRAP2,  RAFT1,  RAPT1,  SKS
Associated Syndromes
Smith-Kingsmore syndrome
Chromosome Band
1p36.22
Associated Disorders
ASD, EP, EPS, ID
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). 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%). Poole et al., 2021 characterized 16 individuals from 12 unrelated families with the MTOR c.5395G>A p.(Glu1799Lys) variant; all 16 individuals presented with intellectual disability and megalencephaly, and behavioral problems were described in 14/16 patients (88%), with autism spectrum disorder/autistic traits being the most frequently observed (10 patients).

Molecular Function

The protein encoded by this gene belongs to a family of phosphatidylinositol kinase-related kinases. These kinases mediate cellular responses to stresses such as DNA damage and nutrient deprivation. This kinase is a component of two distinct complexes, mTORC1, which controls protein synthesis, cell growth and proliferation, and mTORC2, which is a regulator of the actin cytoskeleton, and promotes cell survival and cell cycle progression. This protein acts as the target for the cell-cycle arrest and immunosuppressive effects of the FKBP12-rapamycin complex. Inhibitors of mTOR are used in organ transplants as immunosuppressants, and are being evaluated for their therapeutic potential in SARS-CoV-2 infections. Mutations in this gene are associated with Smith-Kingsmore syndrome and somatic focal cortical dysplasia type II.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to MTOR (35 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 undiagnosed diseases 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 -
19 Support - Chen JS et al. (2021) No -
20 Support - Carmignac V et al. (2021) No ASD, epilepsy/seizures
21 Recent Recommendation - Poole RL et al. (2021) No ASD or autistic features, ID
22 Support - Besterman AD et al. (2021) No ASD, DD, ID, epilepsy/seizures
23 Support - Mitani T et al. (2021) No -
24 Support - Mahjani B et al. (2021) Yes -
25 Support - Li D et al. (2022) Yes -
26 Support - Woodbury-Smith M et al. (2022) Yes -
27 Support - Brea-Fernández AJ et al. (2022) No -
28 Support - N.Y.) (07/2) Yes -
29 Support - Zhou X et al. (2022) Yes -
30 Support - More RP et al. (2023) Yes -
31 Support - Balasar et al. (2023) No -
32 Support - Sanchis-Juan A et al. (2023) No -
33 Support - Mona Abdi et al. (2023) Yes DD, ID
34 Support - Lena H Nguyen et al. (2024) No -
35 Support - Ruohao Wu et al. (2024) Yes -
Rare Variants   (58)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1786+3A>G - splice_region_variant De novo - - 35901164 N.Y.) (07/2)
c.4376C>A p.Ala1459Asp missense_variant - - - 28427592 Hanai S , et al. (2017)
c.1855C>T p.Arg619Cys missense_variant Unknown - - 34968013 Li D et al. (2022)
c.6667C>T p.Gln2223Ter stop_gained Unknown - - 34615535 Mahjani B et al. (2021)
c.6797G>A p.Arg2266His missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.4448G>A p.Cys1483Tyr missense_variant De novo - - 22729223 Lee JH , et al. (2012)
c.4448G>A p.Cys1483Tyr missense_variant Unknown - - 28892148 Gordo G , et al. (2017)
c.5395G>A p.Glu1799Lys missense_variant De novo - - 28892148 Gordo G , et al. (2017)
c.6605T>G p.Phe2202Cys missense_variant Unknown - - 28892148 Gordo G , et al. (2017)
c.6668A>T p.Gln2223Leu missense_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.4379T>C p.Leu1460Pro missense_variant Unknown - - 27159400 Mirzaa GM , et al. (2016)
c.5395G>A p.Glu1799Lys missense_variant De novo - - 27159400 Mirzaa GM , et al. (2016)
c.5809C>T p.Gln1937Ter 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.4785G>A p.Met1595Ile missense_variant De novo - - 28554332 Bowling KM , et al. (2017)
c.5663T>G p.Phe1888Cys missense_variant De novo - - 28554332 Bowling KM , et al. (2017)
c.6981G>A p.Met2327Ile missense_variant De novo - - 28554332 Bowling KM , et al. (2017)
c.4356A>T p.Lys1452Asn missense_variant De novo - - 33833411 Carmignac V et al. (2021)
c.4448G>A p.Cys1483Tyr missense_variant De novo - - 33833411 Carmignac V et al. (2021)
c.4555G>A p.Ala1519Thr missense_variant De novo - - 33833411 Carmignac V et al. (2021)
c.4556C>T p.Ala1519Val missense_variant De novo - - 33833411 Carmignac V et al. (2021)
c.5395G>A p.Glu1799Lys missense_variant De novo - - 33833411 Carmignac V et al. (2021)
c.5930C>T p.Thr1977Ile missense_variant De novo - - 33833411 Carmignac V et al. (2021)
c.6050T>C p.Ile2017Thr missense_variant De novo - - 33833411 Carmignac V et al. (2021)
c.7238G>T p.Ser2413Ile missense_variant De novo - - 33833411 Carmignac V et al. (2021)
c.7255G>A p.Glu2419Lys missense_variant De novo - - 33833411 Carmignac V et al. (2021)
c.7280T>C p.Leu2427Pro missense_variant De novo - - 33833411 Carmignac V et al. (2021)
c.7501A>T p.Ile2501Phe missense_variant De novo - - 33833411 Carmignac V et al. (2021)
c.505-2A>G - splice_site_variant Unknown - Multiplex 28554332 Bowling KM , et al. (2017)
c.4169G>A p.Cys1390Tyr missense_variant De novo - - 34197453 Besterman AD et al. (2021)
c.4184A>G p.Lys1395Arg missense_variant De novo - - 34197453 Besterman AD et al. (2021)
c.7216G>A p.Val2406Met missense_variant De novo - - 34197453 Besterman AD et al. (2021)
c.7570C>A p.Gln2524Lys missense_variant Unknown - - 34197453 Besterman AD et al. (2021)
c.5663T>G p.Phe1888Cys missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.6632A>G p.Asn2211Ser missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.4366T>C p.Trp1456Arg missense_variant Unknown - Unknown 33753861 Chen JS et al. (2021)
c.617G>A p.Arg206His missense_variant De novo - Simplex 29346770 Takata A , et al. (2018)
c.4555G>A p.Ala1519Thr missense_variant De novo - - 29051493 Reijnders MRF , et al. (2017)
c.3777C>T p.His1259%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.3904T>G p.Ser1302Ala missense_variant De novo - Simplex 34582790 Mitani T et al. (2021)
c.1599G>A p.Lys533%3D synonymous_variant Unknown - Simplex 37524782 Balasar et al. (2023)
c.4391A>G p.Asp1464Gly missense_variant De novo - Simplex 37805537 Mona Abdi et al. (2023)
c.5911G>A p.Ala1971Thr missense_variant De novo - Simplex 38764027 Ruohao Wu et al. (2024)
c.2403A>G p.Thr801= splice_site_variant Unknown - Unknown 31130284 Monies D , et al. (2019)
c.3452A>G p.Tyr1151Cys missense_variant Familial - Multiplex 36702863 More RP et al. (2023)
c.4732A>G p.Met1578Val missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.1221C>T p.Phe407%3D synonymous_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.5395G>A p.Glu1799Lys missense_variant De novo - Multiplex 25851998 Baynam G , et al. (2015)
c.6158C>T p.Pro2053Leu missense_variant De novo - Multiplex 31398340 Ruzzo EK , et al. (2019)
c.5395G>A p.Glu1799Lys missense_variant De novo - - 27513193 Farwell Hagman KD , et al. (2016)
c.4306_4307delinsTT p.Ala1436Phe missense_variant Unknown - - 31231135 Bruel AL , et al. (2019)
c.7216G>A p.Val2406Met missense_variant De novo - - 35322241 Brea-Fernández AJ et al. (2022)
c.5081C>A p.Pro1694His missense_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.5395G>A p.Glu1799Lys missense_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.4785G>A p.Met1595Ile missense_variant De novo - Simplex 23934111 Epi4K Consortium , et al. (2013)
c.5395G>A p.Glu1799Lys missense_variant De novo - 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
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

4/1/2021
1
icon
1

Score remained at 1

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
[Comorbidities associated with genetic abnormalities in children with intellectual disability2021] [Clinical spectrum of MTOR-related hypomelanosis of Ito with neurodevelopmental abnormalities2021] [Delineating the Smith-Kingsmore syndrome phenotype: Investigation of 16 patients with the MTOR c.5395G > A p.(Glu1799Lys) missense variant2021]
10/1/2019
3S
icon
1

Decreased from 3S to 1

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%).

Reports Added
[Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population.2019] [Increased diagnostic and new genes identification outcome using research reanalysis of singleton exome sequencing.2019] [Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
7/1/2018
3
icon
3S

Decreased from 3 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%).

Reports Added
[Brain Somatic Mutations in MTOR Disrupt Neuronal Ciliogenesis, Leading to Focal Cortical Dyslamination.2018]
10/1/2017
3
icon
3

Decreased 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).

Reports Added
[Variation in a range of mTOR-related genes associates with intracranial volume and intellectual disability.2017]
4/1/2017
3
icon
3

Decreased 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).

Reports Added
[Germline activating MTOR mutation arising through gonadal mosaicism in two brothers with megalencephaly and neurodevelopmental abnormalities.2015] [De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly.2012] [De novo mutations in epileptic encephalopathies.2013] [A germline MTOR mutation in Aboriginal Australian siblings with intellectual disability, dysmorphism, macrocephaly, and small thoraces.2015] [Decreased mTOR signaling pathway in human idiopathic autism and in rats exposed to valproic acid.2015] [Imbalanced mechanistic target of rapamycin C1 and C2 activity in the cerebellum of Angelman syndrome mice impairs motor function.2015] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Association of MTOR Mutations With Developmental Brain Disorders, Including Megalencephaly, Focal Cortical Dysplasia, and Pigmentary Mosaicism.2016] [Candidate-gene criteria for clinical reporting: diagnostic exome sequencing identifies altered candidate genes among 8% of patients with undiagnose...2016] [Pathologic Active mTOR Mutation in Brain Malformation with Intractable Epilepsy Leads to Cell-Autonomous Migration Delay.2017] [Genomic diagnosis for children with intellectual disability and/or developmental delay.2017]
7/1/2016
3
icon
3

Decreased 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).

Reports Added
[Candidate-gene criteria for clinical reporting: diagnostic exome sequencing identifies altered candidate genes among 8% of patients with undiagnose...2016]
4/1/2016
3
icon
3

Decreased 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).

Reports Added
[Germline activating MTOR mutation arising through gonadal mosaicism in two brothers with megalencephaly and neurodevelopmental abnormalities.2015] [De novo somatic mutations in components of the PI3K-AKT3-mTOR pathway cause hemimegalencephaly.2012] [De novo mutations in epileptic encephalopathies.2013] [A germline MTOR mutation in Aboriginal Australian siblings with intellectual disability, dysmorphism, macrocephaly, and small thoraces.2015] [Decreased mTOR signaling pathway in human idiopathic autism and in rats exposed to valproic acid.2015] [Imbalanced mechanistic target of rapamycin C1 and C2 activity in the cerebellum of Angelman syndrome mice impairs motor function.2015] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Association of MTOR Mutations With Developmental Brain Disorders, Including Megalencephaly, Focal Cortical Dysplasia, and Pigmentary Mosaicism.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.
Original Source
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
Original Source
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).
Original Source
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.
Original Source
Interactome
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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