Human Gene Module / Chromosome 3 / TBL1XR1

TBL1XR1transducin beta like 1 X-linked receptor 1

Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
5 / 16
Rare Variants / Common Variants
21 / 0
Aliases
TBL1XR1, C21,  DC42,  IRA1,  TBLR1
Associated Syndromes
West syndrome, Pierpont syndrome
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
3q26.32
Associated Disorders
DD/NDD, ID, EPS, ASD
Relevance to Autism

De novo variants in this gene were identified in two separate reports using ASD probands from the Simons Simplex Collection (Sanders et al. 2012a, 2012b)

Molecular Function

This gene is a member of the WD40 repeat-containing gene family and shares sequence similarity with transducin (beta)-like 1X-linked (TBL1X). The protein encoded by this gene is thought to be a component of both nuclear receptor corepressor (N-CoR) and histone deacetylase 3 (HDAC 3) complexes, and is required for transcriptional activation by a variety of transcription factors. Mutations in these gene have been associated with some autism spectrum disorders, and one finding suggests that haploinsufficiency of this gene may be a cause of intellectual disability with dysmorphism.

Reports related to TBL1XR1 (16 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. O'Roak BJ , et al. (2012) Yes -
2 Support Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. O'Roak BJ , et al. (2012) Yes -
3 Support De novo deletion of TBL1XR1 in a child with non-specific developmental delay supports its implication in intellectual disability. Tabet AC , et al. (2014) No -
4 Support A girl with West syndrome and autistic features harboring a de novo TBL1XR1 mutation. Saitsu H , et al. (2014) No Epilepsy, autistic features
5 Support A new syndrome of intellectual disability with dysmorphism due to TBL1XR1 deletion. Pons L , et al. (2014) No -
6 Support Large-scale discovery of novel genetic causes of developmental disorders. Deciphering Developmental Disorders Study (2014) No Epilpesy/seizures
7 Recent Recommendation Integrating population variation and protein structural analysis to improve clinical interpretation of missense variation: application to the WD40 ... Laskowski RA , et al. (2016) Yes -
8 Recent Recommendation A specific mutation in TBL1XR1 causes Pierpont syndrome. Heinen CA , et al. (2016) No DD, ID
9 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Lelieveld SH , et al. (2016) No -
10 Support Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Stessman HA , et al. (2017) No -
11 Recent Recommendation Structure of the MeCP2-TBLR1 complex reveals a molecular basis for Rett syndrome and related disorders. Kruusvee V , et al. (2017) Yes -
12 Support A heritable microduplication encompassing TBL1XR1 causes a genomic sister-disorder for the 3q26.32 microdeletion syndrome. Riehmer V , et al. (2017) Yes -
13 Support De novo non-synonymous TBL1XR1 mutation alters Wnt signaling activity. Nishi A , et al. (2017) No -
14 Support Pierpont syndrome associated with the p.Tyr446Cys missense mutation in TBL1XR1. Slavotinek A , et al. (2017) No -
15 Support Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test. Lionel AC , et al. (2017) No -
16 Support Clinical genome sequencing in an unbiased pediatric cohort. Thiffault I , et al. (2018) No DD, hypotonia
Rare Variants   (21)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.845T>C p.Leu282Pro missense_variant De novo - Simplex 22495309 O'Roak BJ , et al. (2012)
c.1189delA p.Ile397SerfsTer19 frameshift_variant De novo - Simplex 23160955 O'Roak BJ , et al. (2012)
- - copy_number_loss De novo - - 24891185 Tabet AC , et al. (2014)
c.209G>A p.Gly70Asp missense_variant De novo - - 25102098 Saitsu H , et al. (2014)
- - copy_number_loss Familial Maternal Multi-generational 25425123 Pons L , et al. (2014)
c.1322A>G p.His441Arg missense_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.1108G>T p.Asp370Tyr missense_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.983A>G p.Asp328Gly missense_variant De novo - - 26740553 Laskowski RA , et al. (2016)
c.1331C>G p.Pro444Arg missense_variant De novo - - 26740553 Laskowski RA , et al. (2016)
c.639T>A p.His213Gln missense_variant De novo - - 26740553 Laskowski RA , et al. (2016)
c.800dupG p.Ile269TyrfsTer8 frameshift_variant De novo - - 26740553 Laskowski RA , et al. (2016)
c.1337A>C p.Tyr446Cys missense_variant De novo - - 26769062 Heinen CA , et al. (2016)
c.1336T>G p.Tyr446Asp missense_variant De novo - - 27479843 Lelieveld SH , et al. (2016)
c.1379G>A p.Gly460Asp missense_variant De novo - - 28191889 Stessman HA , et al. (2017)
c.1107C>A p.Asp369Glu missense_variant De novo - - 28348241 Kruusvee V , et al. (2017)
- - copy_number_gain De novo - Simplex 28574232 Riehmer V , et al. (2017)
- - copy_number_gain Familial Maternal Multi-generational 28574232 Riehmer V , et al. (2017)
c.30C>G p.Phe10Leu missense_variant De novo - Simplex 28588275 Nishi A , et al. (2017)
c.1337A>G p.Tyr446Cys missense_variant De novo - - 28687524 Slavotinek A , et al. (2017)
c.1337A>G p.Tyr446Cys missense_variant De novo - - 28771251 Lionel AC , et al. (2017)
c.1336T>G p.Tyr446Asp missense_variant De novo - - 30008475 Thiffault I , et al. (2018)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

2

Score Delta: Score remained at 2.1

2

Strong Candidate

See all Category 2 Genes

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

7/1/2017
2
icon
2

Score remained at 2

Description

In a screen of 44 genes in 2,446 ASD probands from the Simons Simplex Collection, PMID 23160955 found a de novo LoF mutation in TBL1XR1. A second de novo LoF variant in this gene was identified in a patient from the Deciphering Developmental Disorders (DDD study) presenting with autism and developmental delay (PMID 26740553). A number of de novo missense variants in this gene, including several predicted by computer modelling to disrupt protein folding, have also been identified in patients with autism and/or developmental delay (PMIDs 23160955, 26740553). A recurrent de novo missense variant in TBL1XR1 (p.Tyr446Cys) was identified in six unrelated individuals with Pierpont syndrome (OMIM 602342), a syndrome characterized by developmental delay/intellectual disability, facial dysmorphisms, hearing loss, and abnormal fat distribution (PMID 26769062); however, autism has not been detected in individuals with this syndrome. Kruusvee et al., 2017 demonstrated that two de novo missense variants in TBL1XR1 that had been identified in patients from the DECIPHER database presenting with autism and developmental delay/intellectual disability showed impaired binding to MECP2.

4/1/2017
3
icon
2

Decreased from 3 to 2

Description

In a screen of 44 genes in 2,446 ASD probands from the Simons Simplex Collection, PMID 23160955 found a de novo LoF mutation in TBL1XR1. A second de novo LoF variant in this gene was identified in a patient from the Deciphering Developmental Disorders (DDD study) presenting with autism and developmental delay (PMID 26740553). A number of de novo missense variants in this gene, including several predicted by computer modelling to disrupt protein folding, have also been identified in patients with autism and/or developmental delay (PMIDs 23160955, 26740553). A recurrent de novo missense variant in TBL1XR1 (p.Tyr446Cys) was identified in six unrelated individuals with Pierpont syndrome (OMIM 602342), a syndrome characterized by developmental delay/intellectual disability, facial dysmorphisms, hearing loss, and abnormal fat distribution (PMID 26769062); however, autism has not been detected in individuals with this syndrome. Kruusvee et al., 2017 demonstrated that two de novo missense variants in TBL1XR1 that had been identified in patients from the DECIPHER database presenting with autism and developmental delay/intellectual disability showed impaired binding to MECP2.

1/1/2017
3
icon
3

Decreased from 3 to 3

Description

In a screen of 44 genes in 2,446 ASD probands from the Simons Simplex Collection, PMID 23160955 found a de novo LoF mutation in TBL1XR1. A second de novo LoF variant in this gene was identified in a patient from the Deciphering Developmental Disorders (DDD study) presenting with autism and developmental delay (PMID 26740553). A number of de novo missense variants in this gene, including several predicted by computer modelling to disrupt protein folding, have also been identified in patients with autism and/or developmental delay (PMIDs 23160955, 26740553). A recurrent de novo missense variant in TBL1XR1 (p.Tyr446Cys) was identified in six unrelated individuals with Pierpont syndrome (OMIM 602342), a syndrome characterized by developmental delay/intellectual disability, facial dysmorphisms, hearing loss, and abnormal fat distribution (PMID 26769062); however, autism has not been detected in individuals with this syndrome.

7/1/2016
3
icon
3

Decreased from 3 to 3

Description

In a screen of 44 genes in 2,446 ASD probands from the Simons Simplex Collection, PMID 23160955 found a de novo LoF mutation in TBL1XR1. A second de novo LoF variant in this gene was identified in a patient from the Deciphering Developmental Disorders (DDD study) presenting with autism and developmental delay (PMID 26740553). A number of de novo missense variants in this gene, including several predicted by computer modelling to disrupt protein folding, have also been identified in patients with autism and/or developmental delay (PMIDs 23160955, 26740553). A recurrent de novo missense variant in TBL1XR1 (p.Tyr446Cys) was identified in six unrelated individuals with Pierpont syndrome (OMIM 602342), a syndrome characterized by developmental delay/intellectual disability, facial dysmorphisms, hearing loss, and abnormal fat distribution (PMID 26769062); however, autism has not been detected in individuals with this syndrome.

1/1/2016
4
icon
3

Decreased from 4 to 3

Description

In a screen of 44 genes in 2,446 ASD probands from the Simons Simplex Collection, PMID 23160955 found a de novo LoF mutation in TBL1XR1. A second de novo LoF variant in this gene was identified in a patient from the Deciphering Developmental Disorders (DDD study) presenting with autism and developmental delay (PMID 26740553). A number of de novo missense variants in this gene, including several predicted by computer modelling to disrupt protein folding, have also been identified in patients with autism and/or developmental delay (PMIDs 23160955, 26740553). A recurrent de novo missense variant in TBL1XR1 (p.Tyr446Cys) was identified in six unrelated individuals with Pierpont syndrome (OMIM 602342), a syndrome characterized by developmental delay/intellectual disability, facial dysmorphisms, hearing loss, and abnormal fat distribution (PMID 26769062); however, autism has not been detected in individuals with this syndrome.

1/1/2015
4
icon
4

Decreased from 4 to 4

Description

In a screen of 44 genes in 2,446 ASD probands, PMID 23160955 found a de novo LGD mutation in TBL1XR1

4/1/2014
No data
icon
4

Increased from No data to 4

Description

In a screen of 44 genes in 2,446 ASD probands, PMID 23160955 found a de novo LGD mutation in TBL1XR1

Krishnan Probability Score

Score 0.56252562751927

Ranking 1298/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
ExAC Score

Score 0.99882195242503

Ranking 1104/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Sanders TADA Score

Score 0.10236240603662

Ranking 66/18665 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).
Larsen Cumulative Evidence Score

Score 14

Ranking 141/461 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.
Zhang D Score

Score -0.4137886288163

Ranking 18489/20870 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.
CNVs associated with TBL1XR1(1 CNVs)
3q26.32 11 Deletion-Duplication 15  /  80
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
vif Virion infectivity factor HIV-1 Protein Binding 155459 P69720
WNT3A wingless-type MMTV integration site family, member 3A Human Protein Modification 89780 P56704
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