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
ASD, MCAs, ASD, DD, epilepsy, ID, epilepsy
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 Author, Year
c.148A>G p.Met50Val missense_variant Unknown - Simplex Schaaf CP , et al. (2011)
c.1378G>A p.Ala460Thr missense_variant Unknown - Simplex Schaaf CP , et al. (2011)
c.1597A>C p.Lys533Gln missense_variant Familial Maternal Simplex Schaaf CP , et al. (2011)
c.1609C>T p.Arg537Cys missense_variant Unknown - Simplex Schaaf CP , et al. (2011)
c.1816A>G p.Ile606Val missense_variant Unknown - Simplex Schaaf CP , et al. (2011)
c.2032G>A p.Ala678Thr missense_variant Familial (1 case); unknown (1 case) Maternal (1 case) Simplex Schaaf CP , et al. (2011)
c.2712C>G p.Phe904Leu missense_variant Unknown - Simplex Schaaf CP , et al. (2011)
c.2950G>C p.Glu984Gln missense_variant Familial Paternal Simplex Schaaf CP , et al. (2011)
c.3161C>T p.Pro1054Leu missense_variant Unknown - Simplex Schaaf CP , et al. (2011)
c.3290C>T p.Ala1097Val missense_variant Familial Paternal Simplex Schaaf CP , et al. (2011)
c.3905G>A p.Arg1302Gln missense_variant Unknown - Simplex Schaaf CP , et al. (2011)
c.4273G>A p.Gly1425Arg missense_variant Unknown - Simplex Schaaf CP , et al. (2011)
c.5094C>A p.Ser1698Arg missense_variant Familial Maternal Simplex Schaaf CP , et al. (2011)
c.3845_3853delGCTGCCAAG p.1282_1285del inframe_deletion De novo - Simplex Schaaf CP , et al. (2011)
c.4738C>T p.Arg1580Trp missense_variant De novo - Simplex O'Roak BJ , et al. (2012)
c.433G>A p.Ala145Thr missense_variant - - Multiplex Kelleher RJ 3rd , et al. (2012)
c.618C>T p.(=) synonymous_variant - - Multiplex Kelleher RJ 3rd , et al. (2012)
c.1143G>A p.(=) synonymous_variant - - Multiplex Kelleher RJ 3rd , et al. (2012)
c.1292C>T p.Ala431Val missense_variant - - Multiplex Kelleher RJ 3rd , et al. (2012)
c.1839+6G>A - intron_variant - - Multiplex Kelleher RJ 3rd , et al. (2012)
c.1912G>A p.Val638Met missense_variant - - Multiplex Kelleher RJ 3rd , et al. (2012)
c.2155T>C p.Tyr719His missense_variant - - Multiplex Kelleher RJ 3rd , et al. (2012)
c.2621C>T p.Pro874Leu missense_variant - - Multiplex Kelleher RJ 3rd , et al. (2012)
c.3126G>T p.(=) synonymous_variant - - Multiplex Kelleher RJ 3rd , et al. (2012)
c.3252C>G p.Asp1084Glu missense_variant - - Multiplex Kelleher RJ 3rd , et al. (2012)
c.3827C>T p.Ser1276Phe missense_variant - - Multiplex Kelleher RJ 3rd , et al. (2012)
c.3914C>T p.Pro1305Leu missense_variant - - Multiplex Kelleher RJ 3rd , et al. (2012)
c.3974G>A p.Gly1325Asp missense_variant - - Multiplex Kelleher RJ 3rd , et al. (2012)
c.4051G>A p.Glu1351Lys missense_variant - - Multiplex Kelleher RJ 3rd , et al. (2012)
c.4316G>A p.Gly1439Asp missense_variant - - Multiplex Kelleher RJ 3rd , et al. (2012)
c.4341C>T p.(=) synonymous_variant - - Multiplex Kelleher RJ 3rd , et al. (2012)
c.4460C>G p.Ser1487Cys missense_variant - - Multiplex Kelleher RJ 3rd , et al. (2012)
c.5028G>A p.(=) synonymous_variant - - Multiplex Kelleher RJ 3rd , et al. (2012)
c.5069-8C>T - intron_variant - - Multiplex Kelleher RJ 3rd , et al. (2012)
c.5175G>A p.(=) synonymous_variant - - Multiplex Kelleher RJ 3rd , et al. (2012)
c.*5G>A - 3_prime_UTR_variant - - Multiplex Kelleher RJ 3rd , et al. (2012)
c.*26G>A - 3_prime_UTR_variant - - Multiplex Kelleher RJ 3rd , et al. (2012)
c.190A>G p.Ile64Val missense_variant Familial Paternal Simplex Bahl S , et al. (2013)
c.454C>G p.His152Asp missense_variant Familial Maternal Simplex Bahl S , et al. (2013)
c.1597A>C p.Lys533Gln missense_variant Familial Maternal Simplex Bahl S , et al. (2013)
c.2861A>G p.Lys954Arg missense_variant Familial Paternal Simplex Bahl S , et al. (2013)
c.2950G>C p.Glu984Gln missense_variant Familial Paternal Simplex Bahl S , et al. (2013)
c.4285G>T p.Ala1429Ser missense_variant Familial Both parents Simplex Bahl S , et al. (2013)
c.2032G>A p.Ala678Thr missense_variant Unknown - Unknown Koshimizu E , et al. (2013)
c.1643G>T p.Arg548Met missense_variant De novo - Simplex Krumm N , et al. (2015)
c.3364delC p.Arg1121ValfsTer69 frameshift_variant Unknown - Unknown Lim EC , et al. (2015)
c.700_701del p.Glu234fs frameshift_variant Familial - Multi-generational Hwang SK , et al. (2016)
c.2377G>A p.Glu793Lys missense_variant De novo - - Wang T , et al. (2016)
c.3100G>A p.Val1034Ile missense_variant Familial Maternal - Wang T , et al. (2016)
c.1939G>A p.Asp647Asn missense_variant Familial Paternal - Wang T , et al. (2016)
c.5467A>T p.Lys1823Ter stop_gained De novo - - Stessman HA , et al. (2017)
c.4639G>A p.Val1547Ile missense_variant - - - Lim JS , et al. (2017)
N/A N/A - - - - Smalley SL (1998)
Common Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type Author, Year
c.482-348A>G;c.755-348A>G;c.644-348A>G;c.551-348A> C/T intron_variant - - - 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."

01-01-2017
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.

Reports Added
[h] [T]
CNVs associated with TSC2(2 CNVs)
8p23.3-p21.1 1 Deletion 2  /  1
8p23.3-p23.2 6 Duplication 9  /  10
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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