Human Gene Module / Chromosome 2 / TBR1

TBR1T-box, brain, 1

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
23 / 46
Rare Variants / Common Variants
68 / 1
Aliases
TBR1, TBR-1,  TES-56
Associated Syndromes
-
Chromosome Band
2q24.2
Associated Disorders
DD/NDD, ADHD, ID, EPS, ASD
Relevance to Autism

A number of mutations in the TBR1 gene have been identified in multiple individuals with ASD as described below. Two de novo loss-of-function variants and two de novo missense variants in TBR1 have been identified in simplex ASD cases (PMIDs 22495309, 23160955, 22495311); these variants were not observed in controls or in external databases. Functional analysis in Deriziotis et al., 2014 demonstrated that these four de novo TBR1 variants disrupt multiple aspects of TBR1 function, including interactions with co-regulators such as CASK and/or FOXP2, cellular localization, and transcriptional regulation (PMID 25232744). 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 De Rubeis et al., 2014 identified TBR1 as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% 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). Microdeletions encompassing TBR1 have also been identified in patients with developmental delay/intellectual disability (PMIDs 23112752, 24458984). den Hoed et al., 2018 functionally characterized two previously identified de novo TBR1 missense variants seen in ASD probands (p.Trp271Cys from De Rubeis et al., 2014 and p.Lys389Glu from ORoak et al., 2014) and determined that both variants disrupted multiple aspects of TBR1 function, including cellular localization and interactions with CASK, FOXP1, and FOXP2; the authors of this study also determined that the rare inherited TBR1 missense variant p.Gln418Arg (originally reported in an ASD proband in Deriziotis et al., 2014) disrupted the interaction between TBR1 and BCL11A. Through international data sharing, Nambot et al., 2020 collected data from 25 previously unreported individuals with TBR1 variants and found that autistic features were frequently observed (19/25 individuals), with five individuals receiving a diagnosis of ASD according to DSM-IV and/or ADOS criteria. A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified TBR1 as a gene reaching exome-wide significance (P < 2.5E-06).

Molecular Function

Probable transcriptional regulator involved in developmental processes that is required for normal brain development.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome Informatics
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to TBR1 (46 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Nuclear translocation and transcription regulation by the membrane-associated guanylate kinase CASK/LIN-2 Hsueh YP , et al. (2000) No -
2 Support - Wang GS , et al. (2004) No -
3 Primary Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations O'Roak BJ , et al. (2012) Yes -
4 Support Patterns and rates of exonic de novo mutations in autism spectrum disorders Neale BM , et al. (2012) Yes -
5 Support Investigation of TBR1 Hemizygosity: Four Individuals with 2q24 Microdeletions Traylor RN , et al. (2012) No Epilepsy, PDD, ADHD, autistic features
6 Support Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders O'Roak BJ , et al. (2012) Yes -
7 Recent Recommendation Tbr1 haploinsufficiency impairs amygdalar axonal projections and results in cognitive abnormality Huang TN , et al. (2014) No -
8 Support TBR1 is the candidate gene for intellectual disability in patients with a 2q24.2 interstitial deletion Palumbo O , et al. (2014) No -
9 Support De novo TBR1 mutations in sporadic autism disrupt protein functions Deriziotis P , et al. (2014) Yes -
10 Recent Recommendation Neuronal excitation upregulates Tbr1, a high-confidence risk gene of autism, mediating Grin2b expression in the adult brain Chuang HC , et al. (2014) No -
11 Support De novo mutations in moderate or severe intellectual disability Hamdan FF , et al. (2014) No Autistic features
12 Recent Recommendation Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
13 Support Recurrent de novo mutations implicate novel genes underlying simplex autism risk O'Roak BJ , et al. (2014) Yes -
14 Recent Recommendation T-Brain-1--A Potential Master Regulator in Autism Spectrum Disorders Chuang HC , et al. (2015) No -
15 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission Iossifov I , et al. (2015) Yes -
16 Support Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci Sanders SJ , et al. (2015) Yes -
17 Recent Recommendation TBR1 regulates autism risk genes in the developing neocortex Notwell JH , et al. (2016) No -
18 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability Lelieveld SH et al. (2016) No -
19 Positive Association Microsatellite polymorphisms associated with human behavioural and psychological phenotypes including a gene-environment interaction Bagshaw AT , et al. (2017) No -
20 Support Calcium/calmodulin-dependent serine protein kinase (CASK), a protein implicated in mental retardation and autism-spectrum disorders, interacts with T-Brain-1 (TBR1) to control extinction of associative memory in male mice Huang TN and Hsueh YP (2017) No -
21 Support Genomic diagnosis for children with intellectual disability and/or developmental delay Bowling KM , et al. (2017) No -
22 Support Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains Geisheker MR , et al. (2017) Yes -
23 Support The TBR1-related autistic-spectrum-disorder phenotype and its clinical spectrum McDermott JH , et al. (2017) Yes -
24 Recent recommendation Functional characterization of TBR1 variants in neurodevelopmental disorder den Hoed J , et al. (2018) No -
25 Support Mutations in TBR1 gene leads to cortical malformations and intellectual disability Vegas N , et al. (2018) No Autistic features
26 Recent Recommendation Neonatal Tbr1 Dosage Controls Cortical Layer 6 Connectivity Fazel Darbandi S , et al. (2018) No -
27 Support Increased diagnostic and new genes identification outcome using research reanalysis of singleton exome sequencing Bruel AL , et al. (2019) No ASD
28 Recent Recommendation A TBR1-K228E Mutation Induces Tbr1 Upregulation, Altered Cortical Distribution of Interneurons, Increased Inhibitory Synaptic Transmission, and Autistic-Like Behavioral Deficits in Mice Yook C , et al. (2019) Yes -
29 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
30 Recent recommendation De novo TBR1 variants cause a neurocognitive phenotype with ID and autistic traits: report of 25 new individuals and review of the literature Nambot S , et al. (2020) No ASD or autistic features
31 Support Excess of de novo variants in genes involved in chromatin remodelling in patients with marfanoid habitus and intellectual disability Chevarin M et al. (2020) No Autistic features, marfanoid habitus
32 Support A de novo frameshift pathogenic variant in TBR1 identified in autism without intellectual disability Sapey-Triomphe LA et al. (2020) Yes -
33 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes ID
34 Support - Hiraide T et al. (2021) Yes -
35 Support - Pode-Shakked B et al. (2021) No -
36 Support - Jin C et al. (2021) No -
37 Support - Chen S et al. (2021) Yes Epilepsy/seizures
38 Support - Crespo I et al. (2022) No -
39 Support - Zhang W et al. (2022) Yes -
40 Support - Zhou X et al. (2022) Yes -
41 Recent Recommendation - Sollis E et al. (2022) Yes DD, ID
42 Recent Recommendation - Weinschutz Mendes H et al. (2023) Yes -
43 Support - Sheth F et al. (2023) Yes DD, ID
44 Support - Tamam Khalaf et al. (2024) No -
45 Support - Siavash Fazel Darbandi et al. () Yes -
46 Support - Tsan-Ting Hsu et al. (2024) Yes -
Rare Variants   (68)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - - 32005960 Nambot S , et al. (2020)
- - copy_number_loss De novo - - 23112752 Traylor RN , et al. (2012)
- - copy_number_loss Unknown - - 23112752 Traylor RN , et al. (2012)
- - copy_number_loss De novo - Simplex 24458984 Palumbo O , et al. (2014)
c.571C>T p.Gln191Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.896G>A p.Trp299Ter stop_gained De novo - - 31231135 Bruel AL , et al. (2019)
c.471del p.Tyr157Ter stop_gained Unknown - - 32005960 Nambot S , et al. (2020)
c.553C>T p.Gln185Ter stop_gained De novo - - 32005960 Nambot S , et al. (2020)
c.844C>T p.Gln282Ter stop_gained De novo - - 32005960 Nambot S , et al. (2020)
c.896G>A p.Trp299Ter stop_gained De novo - - 32005960 Nambot S , et al. (2020)
c.280C>T p.Arg94Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.692G>A p.Arg231Lys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1066G>A p.Val356Met missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1174C>T p.Arg392Trp missense_variant De novo - - 33004838 Wang T et al. (2020)
c.1252C>T p.Gln418Ter stop_gained Unknown - Simplex 33004838 Wang T et al. (2020)
c.673A>T p.Ile225Phe missense_variant De novo - - 32005960 Nambot S , et al. (2020)
c.811T>C p.Trp271Arg missense_variant De novo - - 32005960 Nambot S , et al. (2020)
c.812G>C p.Trp271Ser missense_variant De novo - - 32005960 Nambot S , et al. (2020)
c.1118A>G p.Gln373Arg missense_variant De novo - - 32005960 Nambot S , et al. (2020)
c.1155C>G p.Asn385Lys missense_variant De novo - - 32005960 Nambot S , et al. (2020)
c.896G>A p.Trp299Ter stop_gained De novo - Simplex 32277047 Chevarin M et al. (2020)
c.1128+39C>G - intron_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.765T>A p.Asp255Glu missense_variant Unknown - - 28628100 Geisheker MR , et al. (2017)
c.766G>T p.Val256Leu missense_variant Unknown - - 28628100 Geisheker MR , et al. (2017)
c.932T>C p.Leu311Pro missense_variant De novo - - 29288087 McDermott JH , et al. (2017)
c.689del p.Gly230GlufsTer8 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.560del p.Ala187ValfsTer29 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.946G>T p.Gly316Ter stop_gained De novo - Simplex 29288087 McDermott JH , et al. (2017)
c.1175G>T p.Arg392Leu missense_variant Familial Paternal - 33004838 Wang T et al. (2020)
c.1110del p.Ala371ProfsTer10 frameshift_variant De novo - - 33004838 Wang T et al. (2020)
c.1157del p.Pro386LeufsTer22 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.951_953del p.Ser318del inframe_deletion Unknown - - 38438125 Tamam Khalaf et al. (2024)
c.1120A>C p.Asn374His missense_variant De novo - Simplex 22495311 Neale BM , et al. (2012)
c.682A>G p.Lys228Glu missense_variant De novo - Simplex 23160955 O'Roak BJ , et al. (2012)
c.811T>C p.Trp271Arg missense_variant De novo - Simplex 25356899 Hamdan FF , et al. (2014)
c.1177dup p.Asp393GlyfsTer2 frameshift_variant De novo - - 32005960 Nambot S , et al. (2020)
c.1165A>G p.Lys389Glu missense_variant De novo - Simplex 25418537 O'Roak BJ , et al. (2014)
c.813G>T p.Trp271Cys missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.1652dup p.Gln552AlafsTer122 frameshift_variant De novo - - 32005960 Nambot S , et al. (2020)
c.1049dup p.Ser351Ter frameshift_variant De novo - Simplex 23160955 O'Roak BJ , et al. (2012)
c.1120A>T p.Asn374Tyr missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.1066G>A p.Val356Met missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.813G>T p.Trp271Cys missense_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.284A>G p.His95Arg missense_variant Familial Paternal Simplex 37543562 Sheth F et al. (2023)
c.1105_1113del p.Val369_Ala371del inframe_deletion De novo - - 32005960 Nambot S , et al. (2020)
c.713_719del p.Ser238ThrfsTer17 frameshift_variant De novo - - 32005960 Nambot S , et al. (2020)
c.1165A>G p.Lys389Glu missense_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.1132A>T p.Thr378Ser missense_variant De novo - Simplex 34580403 Pode-Shakked B et al. (2021)
c.1660_c.1661insG p.Cys554TrpfsTer120 frameshift_variant De novo - - 34800434 Chen S et al. (2021)
c.1588_1594dup p.Thr532ArgfsTer144 frameshift_variant De novo - - 31231135 Bruel AL , et al. (2019)
c.1588_1594dup p.Thr532ArgfsTer144 frameshift_variant De novo - - 32005960 Nambot S , et al. (2020)
c.1635_1644dup p.Ser549GlyfsTer128 frameshift_variant De novo - - 32005960 Nambot S , et al. (2020)
c.1639_1648dup p.Pro550ArgfsTer127 frameshift_variant De novo - - 32005960 Nambot S , et al. (2020)
c.1653_1654del p.Gln552ValfsTer121 frameshift_variant De novo - - 32005960 Nambot S , et al. (2020)
c.401del p.His134ProfsTer82 frameshift_variant De novo - Simplex 22495309 O'Roak BJ , et al. (2012)
c.91G>C p.Glu31Gln missense_variant Familial Paternal Unknown 25363760 De Rubeis S , et al. (2014)
c.1588_1594dup p.Thr532ArgfsTer144 frameshift_variant De novo - - 28554332 Bowling KM , et al. (2017)
c.1635_1644dup p.Ser549GlyfsTer128 frameshift_variant De novo - - 27479843 Lelieveld SH et al. (2016)
c.1369_1371delinsCA p.Thr457GlnfsTer30 frameshift_variant De novo - - 32005960 Nambot S , et al. (2020)
c.933_934insCAAAGGA p.Thr312GlnfsTer11 frameshift_variant De novo - - 32005960 Nambot S , et al. (2020)
c.443_444del p.His148ProfsTer92 frameshift_variant De novo - Simplex 33644862 Hiraide T et al. (2021)
c.532C>G p.Gln178Glu missense_variant Familial Paternal Simplex 25232744 Deriziotis P , et al. (2014)
c.1648_1657dup p.Tyr553SerfsTer124 frameshift_variant De novo - Simplex 35837997 Zhang W et al. (2022)
c.1253A>G p.Gln418Arg missense_variant Familial Maternal Simplex 25232744 Deriziotis P , et al. (2014)
c.1625C>G p.Pro542Arg missense_variant Familial Paternal Simplex 25232744 Deriziotis P , et al. (2014)
c.26del p.Pro9LeufsTer12 frameshift_variant De novo - Simplex 32948248 Sapey-Triomphe LA et al. (2020)
c.1588_1594dup p.Thr532ArgfsTer144 frameshift_variant De novo - Simplex 30268909 Vegas N , et al. (2018)
c.370_374del p.Phe124ValfsTer18 frameshift_variant Familial Paternal Simplex 34794744 Jin C et al. (2021)
Common Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
- - microsatellite - - - 28158988 Bagshaw AT , et al. (2017)
SFARI Gene score
1

High Confidence

Score Delta: Score remained at 1

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.

1/1/2021
1
icon
1

Score remained at 1

Description

Two de novo LoF variants (one frameshift, one nonsense) and two de novo missense variants in TBR1 have been identified in simplex ASD cases (PMIDs 22495309, 23160955, 22495311); these variants were not observed in controls or in external databases. Functional analysis demonstrated that these four de novo TBR1 variants disrupt multiple aspects of TBR1 function, including interactions with co-regulators such as CASK and/or FOXP2, cellular localization, and transcriptional regulation (PMID 25232744). Microdeletions encompassing TBR1 have also been identified in patients with developmental delay/intellectual disability (PMIDs 23112752, 24458984). 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 TBR1 as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% 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). den Hoed et al., 2018 functionally characterized two previously identified de novo TBR1 missense variants seen in ASD probands (p.Trp271Cys from De Rubeis et al., 2014 and p.Lys389Glu from ORoak et al., 2014) and determined that both variants disrupted multiple aspects of TBR1 function, including cellular localization and interactions with CASK, FOXP1, and FOXP2; the authors of this study also determined that the rare inherited TBR1 missense variant p.Gln418Arg (originally reported in an ASD proband in Deriziotis et al., 2014) disrupted the interaction between TBR1 and BCL11A.

Reports Added
[Genetic and phenotypic analysis of 101 patients with developmental delay or intellectual disability using whole-exome sequencing2021]
10/1/2020
1
icon
1

Score remained at 1

Description

Two de novo LoF variants (one frameshift, one nonsense) and two de novo missense variants in TBR1 have been identified in simplex ASD cases (PMIDs 22495309, 23160955, 22495311); these variants were not observed in controls or in external databases. Functional analysis demonstrated that these four de novo TBR1 variants disrupt multiple aspects of TBR1 function, including interactions with co-regulators such as CASK and/or FOXP2, cellular localization, and transcriptional regulation (PMID 25232744). Microdeletions encompassing TBR1 have also been identified in patients with developmental delay/intellectual disability (PMIDs 23112752, 24458984). 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 TBR1 as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% 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). den Hoed et al., 2018 functionally characterized two previously identified de novo TBR1 missense variants seen in ASD probands (p.Trp271Cys from De Rubeis et al., 2014 and p.Lys389Glu from ORoak et al., 2014) and determined that both variants disrupted multiple aspects of TBR1 function, including cellular localization and interactions with CASK, FOXP1, and FOXP2; the authors of this study also determined that the rare inherited TBR1 missense variant p.Gln418Arg (originally reported in an ASD proband in Deriziotis et al., 2014) disrupted the interaction between TBR1 and BCL11A.

Reports Added
[A de novo frameshift pathogenic variant in TBR1 identified in autism without intellectual disability2020] [Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders2020]
4/1/2020
1
icon
1

Score remained at 1

Description

Two de novo LoF variants (one frameshift, one nonsense) and two de novo missense variants in TBR1 have been identified in simplex ASD cases (PMIDs 22495309, 23160955, 22495311); these variants were not observed in controls or in external databases. Functional analysis demonstrated that these four de novo TBR1 variants disrupt multiple aspects of TBR1 function, including interactions with co-regulators such as CASK and/or FOXP2, cellular localization, and transcriptional regulation (PMID 25232744). Microdeletions encompassing TBR1 have also been identified in patients with developmental delay/intellectual disability (PMIDs 23112752, 24458984). 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 TBR1 as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% 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). den Hoed et al., 2018 functionally characterized two previously identified de novo TBR1 missense variants seen in ASD probands (p.Trp271Cys from De Rubeis et al., 2014 and p.Lys389Glu from ORoak et al., 2014) and determined that both variants disrupted multiple aspects of TBR1 function, including cellular localization and interactions with CASK, FOXP1, and FOXP2; the authors of this study also determined that the rare inherited TBR1 missense variant p.Gln418Arg (originally reported in an ASD proband in Deriziotis et al., 2014) disrupted the interaction between TBR1 and BCL11A.

Reports Added
[Excess of de novo variants in genes involved in chromatin remodelling in patients with marfanoid habitus and intellectual disability2020]
1/1/2020
1
icon
1

Score remained at 1

Description

Two de novo LoF variants (one frameshift, one nonsense) and two de novo missense variants in TBR1 have been identified in simplex ASD cases (PMIDs 22495309, 23160955, 22495311); these variants were not observed in controls or in external databases. Functional analysis demonstrated that these four de novo TBR1 variants disrupt multiple aspects of TBR1 function, including interactions with co-regulators such as CASK and/or FOXP2, cellular localization, and transcriptional regulation (PMID 25232744). Microdeletions encompassing TBR1 have also been identified in patients with developmental delay/intellectual disability (PMIDs 23112752, 24458984). 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 TBR1 as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% 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). den Hoed et al., 2018 functionally characterized two previously identified de novo TBR1 missense variants seen in ASD probands (p.Trp271Cys from De Rubeis et al., 2014 and p.Lys389Glu from ORoak et al., 2014) and determined that both variants disrupted multiple aspects of TBR1 function, including cellular localization and interactions with CASK, FOXP1, and FOXP2; the authors of this study also determined that the rare inherited TBR1 missense variant p.Gln418Arg (originally reported in an ASD proband in Deriziotis et al., 2014) disrupted the interaction between TBR1 and BCL11A.

Reports Added
[Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci.2015] [Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism2020] [De novo TBR1 variants cause a neurocognitive phenotype with ID and autistic traits: report of 25 new individuals and review of the literature.2020]
10/1/2019
1
icon
1

Score remained at 1

New Scoring Scheme
Description

Two de novo LoF variants (one frameshift, one nonsense) and two de novo missense variants in TBR1 have been identified in simplex ASD cases (PMIDs 22495309, 23160955, 22495311); these variants were not observed in controls or in external databases. Functional analysis demonstrated that these four de novo TBR1 variants disrupt multiple aspects of TBR1 function, including interactions with co-regulators such as CASK and/or FOXP2, cellular localization, and transcriptional regulation (PMID 25232744). Microdeletions encompassing TBR1 have also been identified in patients with developmental delay/intellectual disability (PMIDs 23112752, 24458984). 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 TBR1 as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% 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). den Hoed et al., 2018 functionally characterized two previously identified de novo TBR1 missense variants seen in ASD probands (p.Trp271Cys from De Rubeis et al., 2014 and p.Lys389Glu from ORoak et al., 2014) and determined that both variants disrupted multiple aspects of TBR1 function, including cellular localization and interactions with CASK, FOXP1, and FOXP2; the authors of this study also determined that the rare inherited TBR1 missense variant p.Gln418Arg (originally reported in an ASD proband in Deriziotis et al., 2014) disrupted the interaction between TBR1 and BCL11A.

Reports Added
[A TBR1-K228E Mutation Induces Tbr1 Upregulation, Altered Cortical Distribution of Interneurons, Increased Inhibitory Synaptic Transmission, and Aut...2019] [New Scoring Scheme]
7/1/2019
1
icon
1

Score remained at 1

Description

Two de novo LoF variants (one frameshift, one nonsense) and two de novo missense variants in TBR1 have been identified in simplex ASD cases (PMIDs 22495309, 23160955, 22495311); these variants were not observed in controls or in external databases. Functional analysis demonstrated that these four de novo TBR1 variants disrupt multiple aspects of TBR1 function, including interactions with co-regulators such as CASK and/or FOXP2, cellular localization, and transcriptional regulation (PMID 25232744). Microdeletions encompassing TBR1 have also been identified in patients with developmental delay/intellectual disability (PMIDs 23112752, 24458984). 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 TBR1 as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% 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). den Hoed et al., 2018 functionally characterized two previously identified de novo TBR1 missense variants seen in ASD probands (p.Trp271Cys from De Rubeis et al., 2014 and p.Lys389Glu from ORoak et al., 2014) and determined that both variants disrupted multiple aspects of TBR1 function, including cellular localization and interactions with CASK, FOXP1, and FOXP2; the authors of this study also determined that the rare inherited TBR1 missense variant p.Gln418Arg (originally reported in an ASD proband in Deriziotis et al., 2014) disrupted the interaction between TBR1 and BCL11A.

Reports Added
[Increased diagnostic and new genes identification outcome using research reanalysis of singleton exome sequencing.2019]
10/1/2018
1
icon
1

Score remained at 1

Description

Two de novo LoF variants (one frameshift, one nonsense) and two de novo missense variants in TBR1 have been identified in simplex ASD cases (PMIDs 22495309, 23160955, 22495311); these variants were not observed in controls or in external databases. Functional analysis demonstrated that these four de novo TBR1 variants disrupt multiple aspects of TBR1 function, including interactions with co-regulators such as CASK and/or FOXP2, cellular localization, and transcriptional regulation (PMID 25232744). Microdeletions encompassing TBR1 have also been identified in patients with developmental delay/intellectual disability (PMIDs 23112752, 24458984). 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 TBR1 as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% 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). den Hoed et al., 2018 functionally characterized two previously identified de novo TBR1 missense variants seen in ASD probands (p.Trp271Cys from De Rubeis et al., 2014 and p.Lys389Glu from ORoak et al., 2014) and determined that both variants disrupted multiple aspects of TBR1 function, including cellular localization and interactions with CASK, FOXP1, and FOXP2; the authors of this study also determined that the rare inherited TBR1 missense variant p.Gln418Arg (originally reported in an ASD proband in Deriziotis et al., 2014) disrupted the interaction between TBR1 and BCL11A.

Reports Added
[Recurrent de novo mutations implicate novel genes underlying simplex autism risk.2014] [Functional characterization of TBR1 variants in neurodevelopmental disorder.2018] [Mutations in TBR1 gene leads to cortical malformations and intellectual disability.2018] [Neonatal Tbr1 Dosage Controls Cortical Layer 6 Connectivity.2018]
7/1/2017
1
icon
1

Score remained at 1

Description

Two de novo LoF variants (one frameshift, one nonsense) and two de novo missense variants in TBR1 have been identified in simplex ASD cases (PMIDs 22495309, 23160955, 22495311); these variants were not observed in controls or in external databases. Functional analysis demonstrated that these four de novo TBR1 variants disrupt multiple aspects of TBR1 function, including interactions with co-regulators such as CASK and/or FOXP2, cellular localization, and transcriptional regulation (PMID 25232744). Microdeletions encompassing TBR1 have also been identified in patients with developmental delay/intellectual disability (PMIDs 23112752, 24458984). 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 TBR1 as a gene meeting high statistical significance with a FDR ? 0.01, meaning that this gene had a ? 99% 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
[Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains.2017]
4/1/2017
1
icon
1

Score remained at 1

Description

Two de novo LoF variants (one frameshift, one nonsense) and two de novo missense variants in TBR1 have been identified in simplex ASD cases (PMIDs 22495309, 23160955, 22495311); these variants were not observed in controls or in external databases. Functional analysis demonstrated that these four de novo TBR1 variants disrupt multiple aspects of TBR1 function, including interactions with co-regulators such as CASK and/or FOXP2, cellular localization, and transcriptional regulation (PMID 25232744). Microdeletions encompassing TBR1 have also been identified in patients with developmental delay/intellectual disability (PMIDs 23112752, 24458984). 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 TBR1 as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% 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
[Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.2012] [Patterns and rates of exonic de novo mutations in autism spectrum disorders.2012] [Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.2012] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Investigation of TBR1 Hemizygosity: Four Individuals with 2q24 Microdeletions.2012] [TBR1 is the candidate gene for intellectual disability in patients with a 2q24.2 interstitial deletion.2014] [Tbr1 haploinsufficiency impairs amygdalar axonal projections and results in cognitive abnormality.2014] [De novo TBR1 mutations in sporadic autism disrupt protein functions.2014] [Neuronal excitation upregulates Tbr1, a high-confidence risk gene of autism, mediating Grin2b expression in the adult brain.2014] [T-Brain-1 - A Potential Master Regulator in Autism Spectrum Disorders.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [TBR1 regulates autism risk genes in the developing neocortex.2016] [Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016] [Microsatellite polymorphisms associated with human behavioural and psychological phenotypes including a gene-environment interaction.2017] [Nuclear translocation and transcription regulation by the membrane-associated guanylate kinase CASK/LIN-2.2000] [Calcium/calmodulin-dependent serine protein kinase (CASK), a protein implicated in mental retardation and autism-spectrum disorders, interacts with...2017] [De novo mutations in moderate or severe intellectual disability.2014] [Genomic diagnosis for children with intellectual disability and/or developmental delay.2017]
1/1/2017
1
icon
1

Score remained at 1

Description

Two de novo LoF variants (one frameshift, one nonsense) and two de novo missense variants in TBR1 have been identified in simplex ASD cases (PMIDs 22495309, 23160955, 22495311); these variants were not observed in controls or in external databases. Functional analysis demonstrated that these four de novo TBR1 variants disrupt multiple aspects of TBR1 function, including interactions with co-regulators such as CASK and/or FOXP2, cellular localization, and transcriptional regulation (PMID 25232744). Microdeletions encompassing TBR1 have also been identified in patients with developmental delay/intellectual disability (PMIDs 23112752, 24458984). 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 TBR1 as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% 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
[Microsatellite polymorphisms associated with human behavioural and psychological phenotypes including a gene-environment interaction.2017] [Nuclear translocation and transcription regulation by the membrane-associated guanylate kinase CASK/LIN-2.2000] [Calcium/calmodulin-dependent serine protein kinase (CASK), a protein implicated in mental retardation and autism-spectrum disorders, interacts with...2017]
7/1/2016
1
icon
1

Score remained at 1

Description

Two de novo LoF variants (one frameshift, one nonsense) and two de novo missense variants in TBR1 have been identified in simplex ASD cases (PMIDs 22495309, 23160955, 22495311); these variants were not observed in controls or in external databases. Functional analysis demonstrated that these four de novo TBR1 variants disrupt multiple aspects of TBR1 function, including interactions with co-regulators such as CASK and/or FOXP2, cellular localization, and transcriptional regulation (PMID 25232744). Microdeletions encompassing TBR1 have also been identified in patients with developmental delay/intellectual disability (PMIDs 23112752, 24458984). 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 TBR1 as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% 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
[TBR1 regulates autism risk genes in the developing neocortex.2016] [Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016]
1/1/2016
1
icon
1

Score remained at 1

Description

Two de novo LoF variants (one frameshift, one nonsense) and two de novo missense variants in TBR1 have been identified in simplex ASD cases (PMIDs 22495309, 23160955, 22495311); these variants were not observed in controls or in external databases. Functional analysis demonstrated that these four de novo TBR1 variants disrupt multiple aspects of TBR1 function, including interactions with co-regulators such as CASK and/or FOXP2, cellular localization, and transcriptional regulation (PMID 25232744). Microdeletions encompassing TBR1 have also been identified in patients with developmental delay/intellectual disability (PMIDs 23112752, 24458984). 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 TBR1 as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% 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
[Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.2012] [Patterns and rates of exonic de novo mutations in autism spectrum disorders.2012] [Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.2012] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Investigation of TBR1 Hemizygosity: Four Individuals with 2q24 Microdeletions.2012] [TBR1 is the candidate gene for intellectual disability in patients with a 2q24.2 interstitial deletion.2014] [Tbr1 haploinsufficiency impairs amygdalar axonal projections and results in cognitive abnormality.2014] [De novo TBR1 mutations in sporadic autism disrupt protein functions.2014] [Neuronal excitation upregulates Tbr1, a high-confidence risk gene of autism, mediating Grin2b expression in the adult brain.2014] [T-Brain-1 - A Potential Master Regulator in Autism Spectrum Disorders.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015]
1/1/2015
1
icon
1

Score remained at 1

Description

Two de novo LGD variants (one frameshift, one nonsense) and two de novo missense variants in TBR1 have been identified in simplex ASD cases (PMIDs 22495309, 23160955, 22495311); these variants were not observed in controls or in external databases. Functional analysis demonstrated that these four de novo TBR1 variants disrupt multiple aspects of TBR1 function, including interactions with co-regulators such as CASK and/or FOXP2, cellular localization, and transcriptional regulation (PMID 25232744). Microdeletions encompassing TBR1 have also been identified in patients with developmental delay/intellectual disability (PMIDs 23112752, 24458984). 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 TBR1 as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760).

Reports Added
[T-Brain-1 - A Potential Master Regulator in Autism Spectrum Disorders.2015]
10/1/2014
2
icon
1

Decreased from 2 to 1

Description

Two de novo LGD variants (one frameshift, one nonsense) and two de novo missense variants in TBR1 have been identified in simplex ASD cases (PMIDs 22495309, 23160955, 22495311); these variants were not observed in controls or in external databases. Functional analysis demonstrated that these four de novo TBR1 variants disrupt multiple aspects of TBR1 function, including interactions with co-regulators such as CASK and/or FOXP2, cellular localization, and transcriptional regulation (PMID 25232744). Microdeletions encompassing TBR1 have also been identified in patients with developmental delay/intellectual disability (PMIDs 23112752, 24458984). 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 TBR1 as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760).

Reports Added
[Patterns and rates of exonic de novo mutations in autism spectrum disorders.2012] [De novo TBR1 mutations in sporadic autism disrupt protein functions.2014] [Neuronal excitation upregulates Tbr1, a high-confidence risk gene of autism, mediating Grin2b expression in the adult brain.2014] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014]
7/1/2014
No data
icon
2

Increased from No data to 2

Description

Two de novo LGD variants (one frameshift, one nonsense) and two de novo missense variants in TBR1 have been identified in simplex ASD cases (PMIDs 22495309, 23160955, 22495311); these variants were not observed in controls or in external databases. Functional analysis demonstrated that these four de novo TBR1 variants disrupt multiple aspects of TBR1 function, including interactions with co-regulators such as CASK and/or FOXP2, cellular localization, and transcriptional regulation (PMID 25232744). Microdeletions encompassing TBR1 have also been identified in patients with developmental delay/intellectual disability (PMIDs 23112752, 24458984).

4/1/2014
No data
icon
3

Increased from No data to 3

Description

In a screen of 44 genes in 2,446 ASD probands, PMID 23160955 reported 2 de novo LGD in TBR1

Krishnan Probability Score

Score 0.61171905614202

Ranking 193/25841 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 0.99358803746459

Ranking 1629/18225 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
Iossifov Probability Score

Score 0.976

Ranking 47/239 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
Original Source
Sanders TADA Score

Score 0.00015371128216179

Ranking 14/18665 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
Larsen Cumulative Evidence Score

Score 78

Ranking 15/461 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.
Original Source
Zhang D Score

Score 0.43844562288918

Ranking 1046/20870 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
External PIN Data
BioGRIDHuman Protein Reference Database
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
Cd200 CD200 antigen Mouse Direct Regulation 17470 O54901
Il7r interleukin 7 receptor Mouse Direct Regulation 16197 P16872
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