Human Gene Module / Chromosome 16 / TSC2

TSC2tuberous sclerosis 2

Score
S
Syndromic Syndromic
Autism Reports / Total Reports
10 / 23
Rare Variants / Common Variants
53 / 1
Aliases
TSC2, LAM,  TSC4,  FLJ43106
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic, Genetic Association
Chromosome Band
16p13.3
Associated Disorders
ID, EPS, DD/NDD, ASD
Relevance to Autism

This gene has been associated with syndromic autism, where a subpopulation of individuals with a given syndrome develop autism. In particular, genetic association has been found between autism and tuberous sclerosis (and hence the TSC1 and TSC2 genes as well). As well, association with TSC2 and autism has been found in an AGRE cohort (Serajee et al., 2003), and a rare mutation in TSC2 has been identified in an individual with ASD (O’Roak et al., 2012).

Molecular Function

The product of this gene is believed to be a tumor suppressor and is able to stimulate specific GTPases.

Reports related to TSC2 (23 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Tsc tumour suppressor proteins antagonize amino-acid-TOR signalling. Gao X , et al. (2002) No -
2 Positive Association Association of INPP1, PIK3CG, and TSC2 gene variants with autistic disorder: implications for phosphatidylinositol signalling in autism. Serajee FJ , et al. (2003) Yes -
3 Recent Recommendation Neuroepileptic correlates of autistic symptomatology in tuberous sclerosis. Bolton PF (2004) No -
4 Recent Recommendation Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2. Tavazoie SF , et al. (2005) No -
5 Recent Recommendation Reversal of learning deficits in a Tsc2+/- mouse model of tuberous sclerosis. Ehninger D , et al. (2008) No -
6 Recent Recommendation Tuberous sclerosis complex proteins control axon formation. Choi YJ , et al. (2008) No -
7 Recent Recommendation ARD1 stabilization of TSC2 suppresses tumorigenesis through the mTOR signaling pathway. Kuo HP , et al. (2010) No -
8 Support Oligogenic heterozygosity in individuals with high-functioning autism spectrum disorders. Schaaf CP , et al. (2011) Yes -
9 Support Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. O'Roak BJ , et al. (2012) Yes -
10 Support High-throughput sequencing of mGluR signaling pathway genes reveals enrichment of rare variants in autism. Kelleher RJ 3rd , et al. (2012) Yes -
11 Negative association Lack of association of rare functional variants in TSC1/TSC2 genes with autism spectrum disorder. Bahl S , et al. (2013) Yes -
12 Support Performance comparison of bench-top next generation sequencers using microdroplet PCR-based enrichment for targeted sequencing in patients with aut... Koshimizu E , et al. (2013) Yes ID, epilepsy
13 Recent Recommendation Identification of regions critical for the integrity of the TSC1-TSC2-TBC1D7 complex. Santiago Lima AJ , et al. (2014) No -
14 Recent recommendation Loss of mTOR-dependent macroautophagy causes autistic-like synaptic pruning deficits. Tang G , et al. (2014) No -
15 Support Excess of rare, inherited truncating mutations in autism. Krumm N , et al. (2015) Yes -
16 Recent recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
17 Support Next-generation sequencing using a pre-designed gene panel for the molecular diagnosis of congenital disorders in pediatric patients. Lim EC , et al. (2015) No MCAs
18 Support Everolimus improves neuropsychiatric symptoms in a patient with tuberous sclerosis carrying a novel TSC2 mutation. Hwang SK , et al. (2016) No ASD, DD, epilepsy
19 Support De novo genic mutations among a Chinese autism spectrum disorder cohort. Wang T , et al. (2016) Yes -
20 Support Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Stessman HA , et al. (2017) Yes -
21 Support Somatic Mutations in TSC1 and TSC2 Cause Focal Cortical Dysplasia. Lim JS , et al. (2017) No -
22 Highly Cited Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products. van Slegtenhorst M , et al. (1998) No -
23 Primary Autism and tuberous sclerosis. Smalley SL (1998) No ASD
Rare Variants   (53)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.148A>G p.Met50Val missense_variant Unknown - Simplex 21624971 Schaaf CP , et al. (2011)
c.1378G>A p.Ala460Thr missense_variant Unknown - Simplex 21624971 Schaaf CP , et al. (2011)
c.1597A>C p.Lys533Gln missense_variant Familial Maternal Simplex 21624971 Schaaf CP , et al. (2011)
c.1609C>T p.Arg537Cys missense_variant Unknown - Simplex 21624971 Schaaf CP , et al. (2011)
c.1816A>G p.Ile606Val missense_variant Unknown - Simplex 21624971 Schaaf CP , et al. (2011)
c.2032G>A p.Ala678Thr missense_variant Familial (1 case); unknown (1 case) Maternal (1 case) Simplex 21624971 Schaaf CP , et al. (2011)
c.2712C>G p.Phe904Leu missense_variant Unknown - Simplex 21624971 Schaaf CP , et al. (2011)
c.2950G>C p.Glu984Gln missense_variant Familial Paternal Simplex 21624971 Schaaf CP , et al. (2011)
c.3161C>T p.Pro1054Leu missense_variant Unknown - Simplex 21624971 Schaaf CP , et al. (2011)
c.3290C>T p.Ala1097Val missense_variant Familial Paternal Simplex 21624971 Schaaf CP , et al. (2011)
c.3905G>A p.Arg1302Gln missense_variant Unknown - Simplex 21624971 Schaaf CP , et al. (2011)
c.4273G>A p.Gly1425Arg missense_variant Unknown - Simplex 21624971 Schaaf CP , et al. (2011)
c.5094C>A p.Ser1698Arg missense_variant Familial Maternal Simplex 21624971 Schaaf CP , et al. (2011)
c.3845_3853delGCTGCCAAG p.1282_1285del inframe_deletion De novo - Simplex 21624971 Schaaf CP , et al. (2011)
c.4738C>T p.Arg1580Trp missense_variant De novo - Simplex 22495309 O'Roak BJ , et al. (2012)
c.433G>A p.Ala145Thr missense_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.618C>T p.(=) synonymous_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.1143G>A p.(=) synonymous_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.1292C>T p.Ala431Val missense_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.1839+6G>A - intron_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.1912G>A p.Val638Met missense_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.2155T>C p.Tyr719His missense_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.2621C>T p.Pro874Leu missense_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.3126G>T p.(=) synonymous_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.3252C>G p.Asp1084Glu missense_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.3827C>T p.Ser1276Phe missense_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.3914C>T p.Pro1305Leu missense_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.3974G>A p.Gly1325Asp missense_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.4051G>A p.Glu1351Lys missense_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.4316G>A p.Gly1439Asp missense_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.4341C>T p.(=) synonymous_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.4460C>G p.Ser1487Cys missense_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.5028G>A p.(=) synonymous_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.5069-8C>T - intron_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.5175G>A p.(=) synonymous_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.*5G>A - 3_prime_UTR_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.*26G>A - 3_prime_UTR_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.190A>G p.Ile64Val missense_variant Familial Paternal Simplex 23514105 Bahl S , et al. (2013)
c.454C>G p.His152Asp missense_variant Familial Maternal Simplex 23514105 Bahl S , et al. (2013)
c.1597A>C p.Lys533Gln missense_variant Familial Maternal Simplex 23514105 Bahl S , et al. (2013)
c.2861A>G p.Lys954Arg missense_variant Familial Paternal Simplex 23514105 Bahl S , et al. (2013)
c.2950G>C p.Glu984Gln missense_variant Familial Paternal Simplex 23514105 Bahl S , et al. (2013)
c.4285G>T p.Ala1429Ser missense_variant Familial Both parents Simplex 23514105 Bahl S , et al. (2013)
c.2032G>A p.Ala678Thr missense_variant Unknown - Unknown 24066114 Koshimizu E , et al. (2013)
c.1643G>T p.Arg548Met missense_variant De novo - Simplex 25961944 Krumm N , et al. (2015)
c.3364delC p.Arg1121ValfsTer69 frameshift_variant Unknown - Unknown 26666243 Lim EC , et al. (2015)
c.700_701del p.Glu234fs frameshift_variant Familial - Multi-generational 27216612 Hwang SK , et al. (2016)
c.2377G>A p.Glu793Lys missense_variant De novo - - 27824329 Wang T , et al. (2016)
c.3100G>A p.Val1034Ile missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.1939G>A p.Asp647Asn missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.5467A>T p.Lys1823Ter stop_gained De novo - - 28191889 Stessman HA , et al. (2017)
c.4639G>A p.Val1547Ile missense_variant - - - 28215400 Lim JS , et al. (2017)
N/A N/A - - - - 9813776 Smalley SL (1998)
Common Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.482-348A>G;c.755-348A>G;c.644-348A>G;c.551-348A>G C/T intron_variant - - - 14627686 Serajee FJ , et al. (2003)
SFARI Gene score
S

Syndromic

Mutations in TSC2 cause the autosomal dominant disorder tuberous sclerosis (TSC). About 25% of individuals with TSC have autism and 40%-50% meet diagnostic criteria within the autistic spectrum disorders.

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."

07-01-2017
S

Initial score established: S

Description

Mutations in TSC2 cause the autosomal dominant disorder tuberous sclerosis (TSC). About 25% of individuals with TSC have autism and 40%-50% meet diagnostic criteria within the autistic spectrum disorders.

CNVs associated with TSC2(1 CNVs)
16p13.3 38 Deletion-Duplication 58  /  440
Animal Models associated with TSC2(15 Models)
TSC2_10_KO_ATG7_DM Genetic
TSC2_10_KO_ATG7_DM_Rapa RESCUE-Pharmaceutical
TSC2_1_KO_HM Genetic
TSC2_2_KO_HT Genetic
TSC2_3_KO_HT Genetic
TSC2_4_DN_HM Genetic
TSC2_5_CN_KO_HM Genetic
TSC2_6_CN_KO_HT Genetic
TSC2_7_CN_KO_HM Genetic
TSC2_8_KO_HT Genetic
TSC2_8_KO_HT_Rapa-2 RESCUE-Pharmaceutical
TSC2_8_KO_HT_RAPA_H RESCUE-Pharmaceutical
TSC2_8_KO_HT_RAPA_L RESCUE-Pharmaceutical
TSC2_8_KO_HT_RAPA_M RESCUE-Pharmaceutical
TSC2_9_KO_HT_GFP-LC3 Genetic
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
4-Sep septin 4 Human Protein Binding 5414 O43236
AMPK AMP-activated protein kinase alpha subunit Fruit Fly Protein Modification 43904 O18645
ATPsynd ATP synthase subunit d, mitochondrial Fruit Fly Direct Regulation 42291 Q24251
CRB3 crumbs homolog 3 (Drosophila) Human Protein Binding 92359 Q9BUF7
PIP4ks Phosphatidylinositol 5-phosphate 4-kinase type-2 gamma Mouse Direct Regulation 117150 Q91XU3
SERPINI1 serpin peptidase inhibitor, clade I (neuroserpin), member 1 Human Protein Binding 5274 Q99574
SPERT spermatid associated Human Protein Binding 220082 Q8NA61
SRCRB4D scavenger receptor cysteine rich domain containing, group B (4 domains) Human Protein Binding 136853 Q8WTU2
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