Human Gene Module / Chromosome 3 / TBL1XR1

TBL1XR1transducin beta like 1 X-linked receptor 1

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
13 / 34
Rare Variants / Common Variants
51 / 0
EAGLE Score
9.15
Moderate Learn More
Aliases
TBL1XR1, C21,  DC42,  IRA1,  TBLR1
Associated Syndromes
West syndrome, Pierpont syndrome
Chromosome Band
3q26.32
Associated Disorders
DD/NDD, ASD, EPS, ID
Genetic Category
Rare Single Gene Mutation, Syndromic, Functional
Relevance to Autism

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. An additional de novo likely gene-disruptive variant in TBL1XR1 was identified in an ASD proband from the Autism Sequencing Consortium in Satterstrom et al., 2020; subsequent TADA analysis of de novo variants from the Simons Simplex Collection and the Autism Sequencing Consortium and protein-truncating variants from iPSYCH in this report identified TBL1XR1 as a candidate gene with a false discovery rate (FDR) 0.01. 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 TBL1XR1 as a gene reaching exome-wide significance (P < 2.5E-06).

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.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to TBL1XR1 (34 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 domain 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
17 Support TBL1XR1 mutations in Pierpont syndrome are not restricted to the recurrent p.Tyr446Cys mutation Lemattre C , et al. (2018) No Autistic features
18 Support Both rare and common genetic variants contribute to autism in the Faroe Islands Leblond CS , et al. (2019) Yes -
19 Support Variant recurrence in neurodevelopmental disorders: the use of publicly available genomic data identifies clinically relevant pathogenic missense variants Lecoquierre F , et al. (2019) No -
20 Support Increased diagnostic and new genes identification outcome using research reanalysis of singleton exome sequencing Bruel AL , et al. (2019) No -
21 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
22 Support Genotype and Phenotype Correlations for TBL1XR1 in Neurodevelopmental Disorders Quan Y et al. (2020) Yes -
23 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes DD
24 Support - Brunet T et al. (2021) No -
25 Support - Pode-Shakked B et al. (2021) No -
26 Support - Aguilera C et al. (2021) No Epilepsy/seizures, stereotypy
27 Support - Li D et al. (2022) Yes -
28 Support - Hu Y et al. (2022) No -
29 Support - Shen Y et al. (2022) No -
30 Support - Krgovic D et al. (2022) Yes DD
31 Support - Zhou X et al. (2022) Yes -
32 Support - Wu XH et al. (2023) No -
33 Support - Sheth F et al. (2023) Yes DD, ID, epilepsy/seizures
34 Support - Mingyue Ren et al. (2023) No ASD
Rare Variants   (51)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - - 24891185 Tabet AC , et al. (2014)
- - copy_number_gain De novo - Simplex 28574232 Riehmer V , et al. (2017)
c.790C>T p.Gln264Ter stop_gained Unknown - - 34968013 Li D et al. (2022)
c.205-7A>G - splice_region_variant De novo - - 35982159 Zhou X et al. (2022)
c.784T>C p.Leu262%3D missense_variant De novo - - 33004838 Wang T et al. (2020)
c.574A>G p.Thr192Ala missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.319C>T p.Gln107Ter stop_gained De novo - Simplex 35982159 Zhou X et al. (2022)
c.209G>A p.Gly70Asp missense_variant De novo - - 25102098 Saitsu H , et al. (2014)
- - copy_number_gain Familial Maternal Simplex 30675382 Leblond CS , et al. (2019)
c.86G>A p.Gly29Asp missense_variant De novo - Simplex 37171308 Wu XH et al. (2023)
c.1336T>C p.Tyr446His missense_variant De novo - - 31231135 Bruel AL , et al. (2019)
c.1183T>C p.Tyr395His missense_variant De novo - - 35813072 Krgovic D et al. (2022)
c.1337A>C p.Tyr446Ser missense_variant De novo - - 26769062 Heinen CA , et al. (2016)
c.1337A>G p.Tyr446Cys missense_variant De novo - - 28771251 Lionel AC , et al. (2017)
c.1000T>C p.Cys334Arg missense_variant De novo - - 34653234 Aguilera C et al. (2021)
c.1043A>G p.His348Arg missense_variant De novo - - 34653234 Aguilera C et al. (2021)
c.187G>A p.Glu63Lys missense_variant De novo - Simplex 35611576 Shen Y et al. (2022)
c.1107C>A p.Asp369Glu missense_variant De novo - - 28348241 Kruusvee V , et al. (2017)
c.30C>G p.Phe10Leu missense_variant De novo - Simplex 28588275 Nishi A , et al. (2017)
c.1047+1G>C - splice_site_variant De novo - Simplex 37683765 Mingyue Ren et al. (2023)
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.1336T>G p.Tyr446Asp missense_variant De novo - - 30008475 Thiffault I , et al. (2018)
c.639T>A p.His213Gln missense_variant De novo - - 26740553 Laskowski RA , et al. (2016)
c.983A>G p.Asp328Gly missense_variant De novo - - 26740553 Laskowski RA , et al. (2016)
c.679G>A p.Asp227Asn missense_variant De novo - Simplex 37543562 Sheth F et al. (2023)
c.1331C>G p.Pro444Arg missense_variant De novo - - 26740553 Laskowski RA , et al. (2016)
c.1337A>G p.Tyr446Cys missense_variant De novo - - 28687524 Slavotinek A , et al. (2017)
- - copy_number_loss Familial Maternal Multi-generational 25425123 Pons L , et al. (2014)
c.799G>T p.Gly267Cys missense_variant De novo - Unknown 33619735 Brunet T et al. (2021)
c.1336T>C p.Tyr446His missense_variant De novo - - 31036916 Lecoquierre F , et al. (2019)
c.845T>C p.Leu282Pro missense_variant De novo - Simplex 22495309 O'Roak BJ , et al. (2012)
- - copy_number_gain Familial Maternal Multi-generational 28574232 Riehmer V , et al. (2017)
c.974G>A p.Cys325Tyr missense_variant De novo - Simplex 30365874 Lemattre C , et al. (2018)
c.1336T>C p.Tyr446His missense_variant De novo - Simplex 30365874 Lemattre C , et al. (2018)
c.1097C>T p.Ser366Phe missense_variant De novo - Simplex 37683765 Mingyue Ren et al. (2023)
c.1108G>A p.Asp370Asn missense_variant De novo - Simplex 37683765 Mingyue Ren et al. (2023)
c.1184A>G p.Tyr395Cys missense_variant De novo - Simplex 37683765 Mingyue Ren et al. (2023)
c.881C>G XP_005247828.1:p.Ala294Gly missense_variant De novo - - 33004838 Wang T et al. (2020)
c.968A>C XP_005247828.1:p.Asp323Ala missense_variant De novo - - 33004838 Wang T et al. (2020)
c.800dup p.Ile269TyrfsTer8 frameshift_variant De novo - - 26740553 Laskowski RA , et al. (2016)
c.882C>T p.Asp294= synonymous_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.1156T>C XP_005247828.1:p.Trp386Arg missense_variant De novo - - 33004838 Wang T et al. (2020)
c.1409G>T XP_005247828.1:p.Gly470Val missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.389_390del p.Thr130SerfsTer14 frameshift_variant De novo - Simplex 32524419 Quan Y et al. (2020)
c.1189del p.Ile397SerfsTer19 frameshift_variant De novo - Simplex 23160955 O'Roak BJ , et al. (2012)
c.442dup p.Met148AsnfsTer9 frameshift_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.303_304del p.Asp101GlufsTer43 frameshift_variant Unknown - Multiplex 35813072 Krgovic D et al. (2022)
c.597_600del p.Ser199ArgfsTer10 frameshift_variant De novo - Simplex 34580403 Pode-Shakked B et al. (2021)
c.1108G>T p.Asp370Tyr missense_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.1322A>G p.His441Arg missense_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants  

No common variants reported.

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.

4/1/2022
2
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1

Decreased from 2 to 1

1/1/2021
2
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2

Decreased from 2 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.

Reports Added
[De novo variants in neurodevelopmental disorders-experiences from a tertiary care center2021]
10/1/2020
2
icon
2

Decreased from 2 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.

Reports Added
[Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders2020]
7/1/2020
2
icon
2

Decreased from 2 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.

Reports Added
[Genotype and Phenotype Correlations for TBL1XR1 in Neurodevelopmental Disorders2020]
1/1/2020
2
icon
2

Decreased from 2 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.

Reports Added
[Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism2020]
10/1/2019
2
icon
2

Decreased from 2 to 2

New Scoring Scheme
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.

Reports Added
[New Scoring Scheme]
7/1/2019
2
icon
2

Decreased from 2 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.

Reports Added
[Variantrecurrence in neurodevelopmental disorders: the use of publicly available genomic data identifies clinically relevant pathogenic missense v...2019] [Increased diagnostic and new genes identification outcome using research reanalysis of singleton exome sequencing.2019]
1/1/2019
2
icon
2

Decreased from 2 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.

Reports Added
[Both rare and common genetic variants contribute to autism in the Faroe Islands.2019]
10/1/2018
2
icon
2

Decreased from 2 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.

Reports Added
[TBL1XR1 mutations in Pierpont syndrome are not restricted to the recurrent p.Tyr446Cys mutation.2018]
7/1/2018
2
icon
2

Decreased from 2 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.

Reports Added
[Clinical genome sequencing in an unbiased pediatric cohort.2018]
7/1/2017
2
icon
2

Decreased from 2 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.

Reports Added
[A heritable microduplication encompassing TBL1XR1 causes a genomic sister-disorder for the 3q26.32 microdeletion syndrome.2017] [De novo non-synonymous TBL1XR1 mutation alters Wnt signaling activity.2017] [Pierpont syndrome associated with the p.Tyr446Cys missense mutation in TBL1XR1.2017] [Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test.2017]
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.

Reports Added
[Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.2012] [Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.2012] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [De novo deletion of TBL1XR1 in a child with non-specific developmental delay supports its implication in intellectual disability.2014] [A new syndrome of intellectual disability with dysmorphism due to TBL1XR1 deletion.2014] [A girl with West syndrome and autistic features harboring a de novo TBL1XR1 mutation.2014] [Integrating population variation and protein structural analysis to improve clinical interpretation of missense variation: application to the WD40 ...2016] [A specific mutation in TBL1XR1 causes Pierpont syndrome.2016] [Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016] [Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.2017] [Structure of the MeCP2-TBLR1 complex reveals a molecular basis for Rett syndrome and related disorders.2017]
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.

Reports Added
[Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.2017]
7/1/2016
3
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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.

Reports Added
[Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016]
1/1/2016
4
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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.

Reports Added
[Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.2012] [Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.2012] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [De novo deletion of TBL1XR1 in a child with non-specific developmental delay supports its implication in intellectual disability.2014] [A new syndrome of intellectual disability with dysmorphism due to TBL1XR1 deletion.2014] [A girl with West syndrome and autistic features harboring a de novo TBL1XR1 mutation.2014] [Integrating population variation and protein structural analysis to improve clinical interpretation of missense variation: application to the WD40 ...2016] [A specific mutation in TBL1XR1 causes Pierpont syndrome.2016]
1/1/2015
4
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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

Reports Added
[Large-scale discovery of novel genetic causes of developmental disorders.2014] [A new syndrome of intellectual disability with dysmorphism due to TBL1XR1 deletion.2014]
7/1/2014
No data
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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

Reports Added
[Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.2012] [Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.2012] [De novo deletion of TBL1XR1 in a child with non-specific developmental delay supports its implication in intellectual disability.2014] [A girl with West syndrome and autistic features harboring a de novo TBL1XR1 mutation.2014]
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.
Original Source
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
Original Source
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).
Original Source
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.
Original Source
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.
Original Source
External PIN Data
BioGRIDHuman Protein Reference Database
Interactome
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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