Human Gene Module / Chromosome 22 / TCF20

TCF20Transcription factor 20 (AR1)

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
14 / 27
Rare Variants / Common Variants
98 / 0
EAGLE Score
38
Strong Learn More
Aliases
TCF20, RP4-669P10.13-001,  AR1,  SPBP,  TCF-20
Associated Syndromes
-
Chromosome Band
22q13.2
Associated Disorders
ASD
Genetic Category
Rare Single Gene Mutation, Syndromic, Functional
Relevance to Autism

De novo and rare inherited variants in the TCF20 gene were identifed in ASD patients in Babbs et al., 2014, including a pericentric inversion with a breakpoint within TCF20 in two brothers with ASD that was not observed in their parents, and a de novo frameshift variant in a female patient with ASD and moderate intellectual disability. Two additional de novo loss-of-function variants in the TCF20 gene were identified in individuals with intellectual disability and postnatal overgrowth in Schafgen et al., 2016; one of these cases also presented with ASD. Another de novo LoF variant in TCF20 was identified in an ASD proband from a simplex family by whole genome sequencing in Yuen et al., 2017. Torti et al., 2019 reported 27 individuals with TCF20 variants, all of whom had developmental delay/intellectual disability; ASD or autistic features was observed in 69% of cases, attention deficit or hyperactivity in 67%, craniofacial features (with no recognizable facial gestalt) in 67%, structural brain anomalies in 24%, and seizures in 12%. Vetrini et al., 2018 reported pathogenic TCF20 variants in 32 patients and 4 affected parents from 31 unrelated families; patients presented with a phenotype characterized by motor delay (94%), language delay (86%) intellectual disability (75%), dysmorphic features (78%), hypotonia (66%), and ASD and other neurobehavioral abnormalities (66%). Two de novo protein-truncating variants in the TCF20 gene were identified in ASD probands 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 TCF20 as a candidate gene with a false discovery rate (FDR) between 0.01 and 0.05 (0.01 < FDR 0.05). Using proximity-dependent biotinylation (BioID), Zhou et al., 2022 identified a TCF20 complex that interacted with MeCP2 at the chromatin interface; Rett syndrome-causing mutations inMECP2disrupted this interaction. Furthermore, this report demonstrated that reducingTcf20partially rescued the behavioral deficits caused byMECP2 overexpression, and behavioral deficits in Tcf20+/- mice overlapped with those observed in a mouse model of Rett syndrome. Additional de novo loss-of-function variants in the TCF20 gene were reported in ASD probands from the SPARK cohort in Zhou et al., 2022; 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 this report identified TCF20 as a gene reaching exome-wide significance (P < 2.5E-06).

Molecular Function

Transcriptional activator that binds to the regulatory region of MMP3 and thereby controls stromelysin expression. It stimulates the activity of various transcriptional activators such as JUN, SP1, PAX6 and ETS1, suggesting a function as a coactivator.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to TCF20 (27 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary De novo and rare inherited mutations implicate the transcriptional coregulator TCF20/SPBP in autism spectrum disorder Babbs C , et al. (2014) Yes -
2 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No -
3 Recent Recommendation Systems genetics identifies a convergent gene network for cognition and neurodevelopmental disease Johnson MR , et al. (2015) No -
4 Support De novo nonsense and frameshift variants of TCF20 in individuals with intellectual disability and postnatal overgrowth Schfgen J , et al. (2016) No ASD
5 Recent Recommendation Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability Lelieveld SH et al. (2016) No -
6 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
7 Support A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology Vissers LE , et al. (2017) No -
8 Support Genomic diagnosis for children with intellectual disability and/or developmental delay Bowling KM , et al. (2017) Yes -
9 Recent Recommendation Variants in TCF20 in neurodevelopmental disability: description of 27 new patients and review of literature Torti E , et al. (2019) No ASD or autistic features
10 Recent Recommendation De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impairments with similarities to Smith-Magenis syndrome Vetrini F , et al. (2019) No ASD
11 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
12 Support - Pode-Shakked B et al. (2021) No ASD
13 Support - Lévy J et al. (2022) No ASD, ADHD, OCD, ODD, epilepsy/seizures
14 Recent Recommendation - Zhou J et al. (2022) No -
15 Support - Hu C et al. (2022) Yes -
16 Recent Recommendation - Zhou X et al. (2022) Yes -
17 Support - Shimelis H et al. (2023) No -
18 Support - Schneeweiss MR et al. (2022) Yes DD
19 Support - Yuan B et al. (2023) Yes -
20 Support - Spataro N et al. (2023) No Autistic features
21 Support - Huang S et al. (2023) Yes -
22 Support - Wang J et al. (2023) Yes -
23 Support - Cirnigliaro M et al. (2023) Yes -
24 Support - Sheth F et al. (2023) Yes DD, ID
25 Support - et al. () Yes -
26 Support - et al. () Yes ADHD, OCD, ID
27 Support - et al. () No -
Rare Variants   (98)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_gain De novo - - 34904221 Lévy J et al. (2022)
- - copy_number_gain Unknown - - 34904221 Lévy J et al. (2022)
- - inversion De novo - Multiplex 25228304 Babbs C , et al. (2014)
- - copy_number_loss De novo - - 30819258 Vetrini F , et al. (2019)
- - copy_number_loss Unknown - - 30819258 Vetrini F , et al. (2019)
c.454T>G p.Tyr152Asp missense_variant Unknown - - 38003033 et al. ()
- - copy_number_gain De novo - Simplex 34904221 Lévy J et al. (2022)
- - copy_number_gain Familial Maternal - 34904221 Lévy J et al. (2022)
- - copy_number_gain De novo - Multiplex 34904221 Lévy J et al. (2022)
c.364C>T p.Gln122Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.697C>T p.Gln233Ter stop_gained De novo - - 30739909 Torti E , et al. (2019)
c.2155C>T p.Arg719Ter stop_gained De novo - - 30739909 Torti E , et al. (2019)
c.2594C>G p.Ser865Ter stop_gained De novo - - 30739909 Torti E , et al. (2019)
c.4774C>T p.Gln1592Ter stop_gained De novo - - 30739909 Torti E , et al. (2019)
c.4786C>T p.Arg1596Ter stop_gained De novo - - 30739909 Torti E , et al. (2019)
c.5655+1G>A - splice_site_variant Unknown - - 30819258 Vetrini F , et al. (2019)
c.469A>G p.Thr157Ala missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2117G>A p.Arg706His missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.3027T>A p.Tyr1009Ter stop_gained De novo - - 30819258 Vetrini F , et al. (2019)
c.3027T>A p.Tyr1009Ter stop_gained Unknown - - 30819258 Vetrini F , et al. (2019)
c.3805C>T p.Gln1269Ter stop_gained De novo - - 30819258 Vetrini F , et al. (2019)
c.5719C>T p.Arg1907Ter stop_gained De novo - - 30819258 Vetrini F , et al. (2019)
c.385C>T p.Gln129Ter stop_gained De novo - - 27479843 Lelieveld SH et al. (2016)
c.2497C>T p.Gln833Ter stop_gained De novo - - 27479843 Lelieveld SH et al. (2016)
c.1752A>G p.Pro584%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.5725C>T p.His1909Tyr missense_variant De novo - - 30739909 Torti E , et al. (2019)
c.2582_2583del p.Ser861Ter frameshift_variant De novo - - 35741772 Hu C et al. (2022)
c.1036C>T p.Gln346Ter stop_gained De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.5129A>G p.Lys1710Arg missense_variant De novo - - 30819258 Vetrini F , et al. (2019)
c.955C>T p.Gln319Ter stop_gained De novo - Simplex 27436265 Schfgen J , et al. (2016)
c.2224C>T p.Arg742Ter stop_gained De novo - Multiplex 30739909 Torti E , et al. (2019)
c.5486C>T p.Pro1829Leu missense_variant Familial Paternal Simplex 38256266 et al. ()
c.3876_3877del p.Asp1293Ter frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.1707del p.Arg570AspfsTer37 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.1323dup p.Gly442ArgfsTer14 frameshift_variant De novo - - 36881370 Yuan B et al. (2023)
c.1960C>T p.Gln654Ter stop_gained Unknown Not maternal - 30739909 Torti E , et al. (2019)
c.2883C>G p.Tyr961Ter stop_gained Unknown Not maternal - 30739909 Torti E , et al. (2019)
c.3354dup p.Pro1119AlafsTer12 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.364dup p.Gln122ProfsTer12 frameshift_variant De novo - - 30739909 Torti E , et al. (2019)
c.622del p.Leu208TyrfsTer19 frameshift_variant De novo - - 30739909 Torti E , et al. (2019)
c.988C>T p.Gln330Ter stop_gained Unknown Not maternal - 30819258 Vetrini F , et al. (2019)
c.1707del p.Arg570AspfsTer37 frameshift_variant De novo - - 30739909 Torti E , et al. (2019)
c.3486dup p.Cys1163LeufsTer5 frameshift_variant De novo - - 30739909 Torti E , et al. (2019)
c.3605dup p.Pro1203SerfsTer15 frameshift_variant De novo - - 30739909 Torti E , et al. (2019)
c.3760dup p.Arg1254LysfsTer14 frameshift_variant De novo - - 30739909 Torti E , et al. (2019)
c.4943del p.Thr1648LysfsTer13 frameshift_variant De novo - - 30739909 Torti E , et al. (2019)
c.5352del p.Arg1785GlyfsTer97 frameshift_variant De novo - - 30739909 Torti E , et al. (2019)
c.594dup p.Gly199TrpfsTer56 frameshift_variant De novo - - 30819258 Vetrini F , et al. (2019)
c.1520del p.Pro507LeufsTer5 frameshift_variant De novo - - 30819258 Vetrini F , et al. (2019)
c.2785_2789del p.Lys929GlyfsTer4 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.1856del p.Lys619SerfsTer164 frameshift_variant De novo - - 36980980 Spataro N et al. (2023)
c.4894del p.Tyr1632ThrfsTer6 frameshift_variant De novo - - 30819258 Vetrini F , et al. (2019)
c.5430dup p.Ala1811SerfsTer4 frameshift_variant De novo - - 30819258 Vetrini F , et al. (2019)
c.932_933del p.Gln311ArgfsTer22 frameshift_variant De novo - - 30739909 Torti E , et al. (2019)
c.3379del p.Gln1127SerfsTer10 frameshift_variant De novo - - 30819258 Vetrini F , et al. (2019)
c.4231dup p.Glu1411GlyfsTer33 frameshift_variant De novo - - 30819258 Vetrini F , et al. (2019)
c.4549dup p.Asp1517GlyfsTer30 frameshift_variant De novo - - 30819258 Vetrini F , et al. (2019)
c.5537del p.Pro1846LeufsTer36 frameshift_variant Unknown - - 30819258 Vetrini F , et al. (2019)
c.5570dup p.Cys1858LeufsTer58 frameshift_variant De novo - - 30819258 Vetrini F , et al. (2019)
c.2088_2089del p.Glu697AlafsTer2 frameshift_variant De novo - - 30739909 Torti E , et al. (2019)
c.2260C>T p.Gln754Ter stop_gained Familial Maternal Simplex 30819258 Vetrini F , et al. (2019)
c.1208T>A p.Val403Glu missense_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.1261A>T p.Thr421Ser missense_variant De novo - Simplex 36593604 Schneeweiss MR et al. (2022)
c.1323dup p.Gly442ArgfsTer14 frameshift_variant De novo - Simplex 37393044 Wang J et al. (2023)
c.704A>G p.Tyr235Cys missense_variant Familial Maternal Simplex 37543562 Sheth F et al. (2023)
c.1810_1811del p.Val604TrpfsTer21 frameshift_variant De novo - - 30739909 Torti E , et al. (2019)
c.4741_4742del p.Arg1581AlafsTer30 frameshift_variant Unknown - - 30739909 Torti E , et al. (2019)
c.5385_5386del p.Cys1795TrpfsTer14 frameshift_variant De novo - - 30739909 Torti E , et al. (2019)
c.2327_2328del p.Gln776ArgfsTer5 frameshift_variant De novo - - 30819258 Vetrini F , et al. (2019)
c.889_890del p.Met297GlufsTer4 frameshift_variant De novo - - 27479843 Lelieveld SH et al. (2016)
c.3518del p.Lys1173ArgfsTer5 frameshift_variant De novo - Simplex 25228304 Babbs C , et al. (2014)
c.4670C>T p.Pro1557Leu missense_variant Familial Maternal Simplex 25228304 Babbs C , et al. (2014)
c.4670C>T p.Pro1557Leu missense_variant Familial Paternal Simplex 25228304 Babbs C , et al. (2014)
c.5652_5653del p.Glu1884AspfsTer31 frameshift_variant Unknown - - 30819258 Vetrini F , et al. (2019)
c.1536_1537insGT p.Ser513ValfsTer8 frameshift_variant Unknown - - 36475376 Shimelis H et al. (2023)
c.1534A>G p.Lys512Glu missense_variant De novo - Extended multiplex 25228304 Babbs C , et al. (2014)
c.5385_5386del p.Cys1795TrpfsTer14 frameshift_variant De novo - - 28554332 Bowling KM , et al. (2017)
c.558G>A p.Gln186%3D stop_gained Familial Maternal Multiplex 36593604 Schneeweiss MR et al. (2022)
c.4670C>T p.Pro1557Leu missense_variant Familial Paternal Multiplex 25228304 Babbs C , et al. (2014)
c.3633_3634insGT p.Tyr1212ValfsTer13 frameshift_variant De novo - - 30819258 Vetrini F , et al. (2019)
c.5511_5512insGC p.Leu1838AlafsTer45 frameshift_variant De novo - - 30819258 Vetrini F , et al. (2019)
c.5529_5530insTG p.Glu1844TrpfsTer39 frameshift_variant De novo - - 30819258 Vetrini F , et al. (2019)
c.3837del p.Asp1280IlefsTer71 frameshift_variant De novo - Simplex 27436265 Schfgen J , et al. (2016)
c.3889_3890insT p.Asn1297IlefsTer17 frameshift_variant De novo - - 28333917 Vissers LE , et al. (2017)
c.5164_5173del p.Gly1722IlefsTer157 frameshift_variant De novo - - 27479843 Lelieveld SH et al. (2016)
c.5719C>T p.Arg1907Ter stop_gained De novo - - 25533962 Deciphering Developmental Disorders Study (2014)
c.3605dup p.Pro1203SerfsTer15 frameshift_variant Unknown Not maternal - 30819258 Vetrini F , et al. (2019)
c.2512_2515del p.Asp838IlefsTer9 frameshift_variant Unknown Not maternal - 30739909 Torti E , et al. (2019)
c.5221_5222del p.Arg1741GlyfsTer9 frameshift_variant De novo - Simplex 34580403 Pode-Shakked B et al. (2021)
c.2553_2554insA p.Ser852IlefsTer4 frameshift_variant De novo - Multiplex 37506195 Cirnigliaro M et al. (2023)
c.3943_3944del p.Asp1315PhefsTer10 frameshift_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.3292_3293insT p.Lys1098IlefsTer33 frameshift_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.1839_1872del p.Met613IlefsTer159 frameshift_variant Familial Paternal Simplex 37303953 Huang S et al. (2023)
c.3849_3850insTC p.Leu1284SerfsTer68 frameshift_variant De novo - Simplex 34580403 Pode-Shakked B et al. (2021)
c.311_312insCACC p.Gln105ThrfsTer30 frameshift_variant Familial Maternal Simplex 30819258 Vetrini F , et al. (2019)
c.3803_3804del p.Arg1268ThrfsTer9 frameshift_variant Unknown Not maternal Multiplex 30739909 Torti E , et al. (2019)
c.2685del p.Arg896GlyfsTer9 frameshift_variant Familial Maternal Multi-generational 30819258 Vetrini F , et al. (2019)
c.5732del p.Pro1911ArgfsTer17 frameshift_variant Familial Paternal Multi-generational 30819258 Vetrini F , et al. (2019)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

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.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

1/1/2020
1
icon
1

Score remained at 1

Description

De novo and rare inherited variants in the TCF20 gene were identifed in ASD patients in Babbs et al., 2014, including a pericentric inversion with a breakpoint within TCF20 in two brothers with ASD that was not observed in their parents, and a de novo frameshift variant in a female patient with ASD and moderate intellectual disability. Two additional de novo loss-of-function variants in the TCF20 gene were identified in individuals with intellectual disability and postnatal overgrowth in Schafgen et al., 2016; one of these cases also presented with ASD. Another de novo LoF variant in TCF20 was identified in an ASD proband from a simplex family by whole genome sequencing in Yuen et al., 2017. Torti et al., 2019 reported 27 individuals with TCF20 variants, all of whom had developmental delay/intellectual disability; ASD or autistic features was observed in 69% of cases, attention deficit or hyperactivity in 67%, craniofacial features (with no recognizable facial gestalt) in 67%, structural brain anomalies in 24%, and seizures in 12%. Vetrini et al., 2018 reported pathogenic TCF20 variants in 32 patients and 4 affected parents from 31 unrelated families; patients presented with a phenotype characterized by motor delay (94%), language delay (86%) intellectual disability (75%), dysmorphic features (78%), hypotonia (66%), and ASD and other neurobehavioral abnormalities (66%).

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

Decreased from 2S to 1

New Scoring Scheme
Description

De novo and rare inherited variants in the TCF20 gene were identifed in ASD patients in Babbs et al., 2014, including a pericentric inversion with a breakpoint within TCF20 in two brothers with ASD that was not observed in their parents, and a de novo frameshift variant in a female patient with ASD and moderate intellectual disability. Two additional de novo loss-of-function variants in the TCF20 gene were identified in individuals with intellectual disability and postnatal overgrowth in Schafgen et al., 2016; one of these cases also presented with ASD. Another de novo LoF variant in TCF20 was identified in an ASD proband from a simplex family by whole genome sequencing in Yuen et al., 2017. Torti et al., 2019 reported 27 individuals with TCF20 variants, all of whom had developmental delay/intellectual disability; ASD or autistic features was observed in 69% of cases, attention deficit or hyperactivity in 67%, craniofacial features (with no recognizable facial gestalt) in 67%, structural brain anomalies in 24%, and seizures in 12%. Vetrini et al., 2018 reported pathogenic TCF20 variants in 32 patients and 4 affected parents from 31 unrelated families; patients presented with a phenotype characterized by motor delay (94%), language delay (86%) intellectual disability (75%), dysmorphic features (78%), hypotonia (66%), and ASD and other neurobehavioral abnormalities (66%).

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

Decreased from 2 to 2S

Description

De novo and rare inherited variants in the TCF20 gene were identifed in ASD patients in Babbs et al., 2014, including a pericentric inversion with a breakpoint within TCF20 in two brothers with ASD that was not observed in their parents, and a de novo frameshift variant in a female patient with ASD and moderate intellectual disability. Two additional de novo loss-of-function variants in the TCF20 gene were identified in individuals with intellectual disability and postnatal overgrowth in Schafgen et al., 2016; one of these cases also presented with ASD. Another de novo LoF variant in TCF20 was identified in an ASD proband from a simplex family by whole genome sequencing in Yuen et al., 2017. Torti et al., 2019 reported 27 individuals with TCF20 variants, all of whom had developmental delay/intellectual disability; ASD or autistic features was observed in 69% of cases, attention deficit or hyperactivity in 67%, craniofacial features (with no recognizable facial gestalt) in 67%, structural brain anomalies in 24%, and seizures in 12%. Vetrini et al., 2018 reported pathogenic TCF20 variants in 32 patients and 4 affected parents from 31 unrelated families; patients presented with a phenotype characterized by motor delay (94%), language delay (86%) intellectual disability (75%), dysmorphic features (78%), hypotonia (66%), and ASD and other neurobehavioral abnormalities (66%).

Reports Added
[Variants in TCF20 in neurodevelopmental disability: description of 27 new patients and review of literature.2019] [De novo and inherited TCF20 pathogenic variants are associated with intellectual disability, dysmorphic features, hypotonia, and neurological impai...2019]
4/1/2017
3
icon
2

Decreased from 3 to 2

Description

De novo and rare inherited variants in the TCF20 gene were identifed in ASD patients in Babbs et al., 2014, including a pericentric inversion with a breakpoint within TCF20 in two brothers with ASD that was not observed in their parents, and a de novo frameshift variant in a female patient with ASD and moderate intellectual disability. Two additional de novo loss-of-function variants in the TCF20 gene were identified in individuals with intellectual disability and postnatal overgrowth in Schafgen et al., 2016; one of these cases also presented with ASD. Another de novo LoF variant in TCF20 was identified in an ASD proband from a simplex family by whole genome sequencing in Yuen et al., 2017

Reports Added
[De novo and rare inherited mutations implicate the transcriptional coregulator TCF20/SPBP in autism spectrum disorder.2014] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Systems genetics identifies a convergent gene network for cognition and neurodevelopmental disease.2015] [De novo nonsense and frameshift variants of TCF20 in individuals with intellectual disability and postnatal overgrowth.2016] [Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016] [Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder2017] [A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology.2017] [Genomic diagnosis for children with intellectual disability and/or developmental delay.2017]
7/1/2016
icon
3

Increased from to 3

Description

De novo and rare inherited variants in the TCF20 gene were identifed in ASD patients in Babbs et al., 2014, including a pericentric inversion with a breakpoint within TCF20 in two brothers with ASD that was not observed in their parents, and a de novo frameshift variant in a female patient with ASD and moderate intellectual disability. Two additional de novo loss-of-function variants in the TCF20 gene were identified in individuals with intellectual disability and postnatal overgrowth in Schafgen et al., 2016; one of these cases also presented with ASD.

Reports Added
[De novo nonsense and frameshift variants of TCF20 in individuals with intellectual disability and postnatal overgrowth.2016] [Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016]
Krishnan Probability Score

Score 0.49542793257762

Ranking 2978/25841 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 0.99997793427612

Ranking 517/18225 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 0.93819201144901

Ranking 13779/18665 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 17.5

Ranking 118/461 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 0.49115183504

Ranking 582/20870 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
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