Human Gene Module / Chromosome 17 / KDM6B

KDM6BLysine (K)-specific demethylase 6B

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
13 / 22
Rare Variants / Common Variants
131 / 0
EAGLE Score
13.75
Strong Learn More
Aliases
KDM6B, JMJD3
Associated Syndromes
-
Chromosome Band
17p13.1
Associated Disorders
DD/NDD, ASD
Genetic Category
Rare Single Gene Mutation, Syndromic, Functional
Relevance to Autism

Two de novo LoF variants in the KDM6B gene (one frameshift, one splice-site) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768). Additional de novo likely gene-disruptive/protein-truncating variants and/or damaging missense variants in KDM6B were identified in ASD probands from the SPARK cohort and the Autism Sequencing Consortium in Feliciano et al., 2019 and Satterstrom et al., 2020, respectively; furthermore, transmission and de novo association (TADA) analysis in both reports identified KDM6B 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 KDM6B as a gene reaching exome-wide significance (P < 2.5E-06).

Molecular Function

This gene encodes a histone demethylase that specifically demethylates 'Lys-27' of histone H3, thereby playing a central role in histone code. Plays a central role in regulation of posterior development, by regulating HOX gene expression.

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 KDM6B (22 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary De novo gene disruptions in children on the autistic spectrum Iossifov I , et al. (2012) Yes -
2 Recent Recommendation Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
3 Recent Recommendation The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
4 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission Iossifov I , et al. (2015) Yes -
5 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability Lelieveld SH et al. (2016) No -
6 Support Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders Reuter MS , et al. (2017) No Sleep disturbances, aggressive behavior
7 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
8 Support Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands Jin SC , et al. (2017) No Neurodevelopmental disorders (NDD)
9 Recent recommendation Genetic variants in the KDM6B gene are associated with neurodevelopmental delays and dysmorphic features Stolerman ES , et al. (2019) No ASD
10 Support Pathogenicity and functional impact of non-frameshifting insertion/deletion variation in the human genome Pagel KA , et al. (2019) Yes -
11 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
12 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
13 Support - Mahjani B et al. (2021) Yes -
14 Support - Singh T et al. (2022) No -
15 Support - Gao Y et al. (2022) Yes ADHD
16 Support - Hu C et al. (2022) Yes -
17 Support - Krgovic D et al. (2022) No Autistic behavior, stereotypy
18 Support - Zhou X et al. (2022) Yes -
19 Support - Han X et al. (2022) No ASD
20 Recent Recommendation - Rots D et al. (2023) No ASD, ADHD, ID, epilepsy/seizures
21 Support - Cirnigliaro M et al. (2023) Yes -
22 Support - et al. () No Autistic features
Rare Variants   (131)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.445C>T p.Arg149Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.685C>T p.Arg229Ter stop_gained De novo - - 37196654 Rots D et al. (2023)
c.4165+5G>A - splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
c.2851C>T p.Arg951Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.2923C>T p.Arg975Ter stop_gained De novo - - 37196654 Rots D et al. (2023)
c.4708G>T p.Glu1570Ter stop_gained De novo - - 28991257 Jin SC , et al. (2017)
c.2134C>T p.Gln712Ter stop_gained Unknown - - 34615535 Mahjani B et al. (2021)
c.1484G>A p.Arg495Gln missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.138-1G>A - splice_site_variant De novo - Unknown 37196654 Rots D et al. (2023)
c.225T>A p.Tyr75Ter stop_gained De novo - - 31124279 Stolerman ES , et al. (2019)
c.3529C>T p.Pro1177Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.4720T>C p.Tyr1574His missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1257+2_1257+3del - splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
c.403C>T p.Arg135Ter stop_gained De novo - Simplex 35982159 Zhou X et al. (2022)
c.403C>T p.Arg135Ter stop_gained De novo - Simplex 37196654 Rots D et al. (2023)
c.445C>T p.Arg149Ter stop_gained De novo - Simplex 37196654 Rots D et al. (2023)
c.3944+1G>A - splice_site_variant De novo - Simplex 37196654 Rots D et al. (2023)
c.4737+1G>A - splice_site_variant De novo - Simplex 37196654 Rots D et al. (2023)
c.445C>T p.Arg149Ter stop_gained De novo - - 31124279 Stolerman ES , et al. (2019)
c.1483C>T p.Arg495Ter stop_gained De novo - Simplex 37196654 Rots D et al. (2023)
c.2448C>G p.Tyr816Ter stop_gained De novo - Simplex 37196654 Rots D et al. (2023)
c.2572C>T p.Gln858Ter stop_gained De novo - Simplex 37196654 Rots D et al. (2023)
c.2923C>T p.Arg975Ter stop_gained De novo - Simplex 37196654 Rots D et al. (2023)
c.2125G>T p.Glu709Ter stop_gained Unknown - Unknown 37196654 Rots D et al. (2023)
c.2134C>T p.Gln712Ter stop_gained Unknown - Unknown 37196654 Rots D et al. (2023)
c.4431G>A p.Trp1477Ter stop_gained De novo - Simplex 37196654 Rots D et al. (2023)
c.4500C>A p.Tyr1500Ter stop_gained De novo - Simplex 37196654 Rots D et al. (2023)
c.496C>T p.Arg166Ter stop_gained Unknown - Multiplex 37196654 Rots D et al. (2023)
c.4165+2T>A - splice_site_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.3674-2A>G - splice_site_variant De novo - Multiplex 37196654 Rots D et al. (2023)
c.3730G>T p.Glu1244Ter stop_gained De novo - - 31124279 Stolerman ES , et al. (2019)
c.138-2A>G - splice_site_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.3281C>A p.Ser1094Ter stop_gained Familial Paternal - 37196654 Rots D et al. (2023)
c.2705del p.Leu902HisfsTer13 frameshift_variant De novo - Simplex 38326731 et al. ()
c.3762_3764del p.Asp1254del inframe_deletion De novo - - 35982159 Zhou X et al. (2022)
c.4783C>T p.Arg1595Cys missense_variant De novo - - 31452935 Feliciano P et al. (2019)
c.1264G>A p.Ala422Thr missense_variant De novo - Simplex 37196654 Rots D et al. (2023)
c.4696C>A p.Arg1566Ser missense_variant De novo - - 27479843 Lelieveld SH et al. (2016)
c.4118T>C p.Met1373Thr missense_variant De novo - Simplex 37196654 Rots D et al. (2023)
c.4193C>A p.Ser1398Tyr missense_variant De novo - Simplex 37196654 Rots D et al. (2023)
c.4254G>T p.Trp1418Cys missense_variant De novo - Simplex 37196654 Rots D et al. (2023)
c.4540A>G p.Met1514Val missense_variant De novo - Simplex 37196654 Rots D et al. (2023)
c.4568G>C p.Arg1523Pro missense_variant De novo - Simplex 37196654 Rots D et al. (2023)
c.4696C>A p.Arg1566Ser missense_variant De novo - Simplex 37196654 Rots D et al. (2023)
c.4724G>C p.Cys1575Ser missense_variant De novo - Simplex 37196654 Rots D et al. (2023)
c.4750A>C p.Asn1584His missense_variant De novo - Simplex 37196654 Rots D et al. (2023)
c.4895A>G p.Asp1632Gly missense_variant De novo - Simplex 37196654 Rots D et al. (2023)
c.4222T>C p.Cys1408Arg missense_variant De novo - Unknown 37196654 Rots D et al. (2023)
c.3992A>G p.Asn1331Ser missense_variant De novo - - 31124279 Stolerman ES , et al. (2019)
c.4136A>C p.Tyr1379Ser missense_variant De novo - - 31124279 Stolerman ES , et al. (2019)
c.2331dup p.Pro778ThrfsTer79 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.2970dup p.Lys991Ter frameshift_variant De novo - Simplex 37196654 Rots D et al. (2023)
c.4468+5G>C - splice_site_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.3535dup p.Glu1179GlyfsTer77 frameshift_variant De novo - - 37196654 Rots D et al. (2023)
c.3444T>G p.Asn1148Lys missense_variant De novo - Multiplex 37196654 Rots D et al. (2023)
c.2781_2794del p.Val928HisfsTer2 frameshift_variant Unknown - - 35741772 Hu C et al. (2022)
c.325C>T p.Leu109Phe missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.523C>T p.Gln175Ter stop_gained Unknown Not maternal Simplex 37196654 Rots D et al. (2023)
c.3762_3764del p.Asp1254del inframe_deletion De novo - Simplex 37196654 Rots D et al. (2023)
c.4187_4189del p.Phe1396del inframe_deletion De novo - Unknown 37196654 Rots D et al. (2023)
c.343C>T p.Gln115Ter stop_gained Familial Maternal Simplex 28263302 C Yuen RK et al. (2017)
c.1069G>A p.Gly357Arg missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1105C>T p.Arg369Trp missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2626G>A p.Gly876Arg missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2012_2013del p.Phe671Ter frameshift_variant De novo - Simplex 37196654 Rots D et al. (2023)
c.4174G>A p.Glu1392Lys missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.3478C>T p.Leu1160Phe missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3626G>A p.Arg1209Gln missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.4369C>G p.Arg1457Gly missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.4420G>A p.Ala1474Thr missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.4571C>T p.Thr1524Met missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1991C>T p.Pro664Leu missense_variant Familial Maternal Simplex 36671766 Han X et al. (2022)
c.2282C>G p.Thr761Ser missense_variant Familial Paternal Simplex 36671766 Han X et al. (2022)
c.3047G>A p.Arg1016Gln missense_variant Familial Maternal Simplex 36671766 Han X et al. (2022)
c.419dup p.Ala141ArgfsTer2 frameshift_variant Familial Paternal - 37196654 Rots D et al. (2023)
c.1439dup p.Pro481ThrfsTer29 frameshift_variant De novo - Simplex 37196654 Rots D et al. (2023)
c.1537dup p.Arg513ProfsTer42 frameshift_variant De novo - Simplex 37196654 Rots D et al. (2023)
c.2598del p.Ser867ArgfsTer27 frameshift_variant De novo - Simplex 37196654 Rots D et al. (2023)
c.2699del p.Pro900HisfsTer15 frameshift_variant De novo - Simplex 37196654 Rots D et al. (2023)
c.3300del p.Lys1101ArgfsTer3 frameshift_variant De novo - Simplex 37196654 Rots D et al. (2023)
c.283G>A p.Gly95Ser missense_variant Familial Maternal Multiplex 37196654 Rots D et al. (2023)
c.2685del p.Thr896ProfsTer19 frameshift_variant De novo - - 31124279 Stolerman ES , et al. (2019)
c.3085dup p.Gln1029ProfsTer4 frameshift_variant De novo - - 31124279 Stolerman ES , et al. (2019)
c.4590del p.Asp1531ThrfsTer5 frameshift_variant De novo - - 31124279 Stolerman ES , et al. (2019)
c.4186T>A p.Phe1396Ile missense_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.2722C>T p.Arg908Cys missense_variant Familial Paternal Multiplex 36671766 Han X et al. (2022)
c.2865del p.Ala956HisfsTer135 frameshift_variant Unknown - Simplex 37196654 Rots D et al. (2023)
c.3046dup p.Arg1016ProfsTer17 frameshift_variant De novo - Simplex 37196654 Rots D et al. (2023)
c.4733del p.Cys1578SerfsTer11 frameshift_variant De novo - Simplex 37196654 Rots D et al. (2023)
c.4420G>A p.Ala1474Thr missense_variant De novo - Multiplex 37506195 Cirnigliaro M et al. (2023)
c.2477C>A p.Ser826Tyr missense_variant Unknown Not paternal Simplex 36671766 Han X et al. (2022)
c.1769del p.Pro590GlnfsTer13 frameshift_variant Familial Maternal - 37196654 Rots D et al. (2023)
c.3196_3199dup p.Ala1067ValfsTer31 frameshift_variant De novo - - 35813072 Krgovic D et al. (2022)
c.1645_1650del p.Pro549_Thr550del inframe_deletion De novo - Simplex 37196654 Rots D et al. (2023)
c.654_655del p.Glu220GlyfsTer16 frameshift_variant De novo - Simplex 37196654 Rots D et al. (2023)
c.3038del p.Lys1013ArgfsTer78 frameshift_variant De novo - Multiplex 37196654 Rots D et al. (2023)
c.578del p.Gly193GlufsTer5 frameshift_variant De novo - Simplex 22542183 Iossifov I , et al. (2012)
c.28G>A p.Ala10Thr missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.4708G>C p.Glu1570Gln missense_variant Unknown Not maternal Simplex 37196654 Rots D et al. (2023)
c.2690_2703del p.Gln897ProfsTer9 frameshift_variant De novo - Simplex 37196654 Rots D et al. (2023)
c.259C>T p.His87Tyr missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.1229_1233dup p.Gly412SerfsTer77 frameshift_variant De novo - Simplex 37196654 Rots D et al. (2023)
c.1260_1270del p.Gly421LeufsTer85 frameshift_variant De novo - Simplex 37196654 Rots D et al. (2023)
c.1416_1417del p.Cys473SerfsTer36 frameshift_variant De novo - Simplex 37196654 Rots D et al. (2023)
c.596G>A p.Arg199Gln missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.982C>T p.Arg328Trp missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.3334_3335del p.Ser1112TrpfsTer2 frameshift_variant De novo - - 31124279 Stolerman ES , et al. (2019)
c.1085_1088del p.Glu362AlafsTer124 frameshift_variant De novo - Simplex 37196654 Rots D et al. (2023)
c.3564_3567del p.Tyr1189TrpfsTer25 frameshift_variant De novo - Simplex 37196654 Rots D et al. (2023)
c.3911_3912del p.Glu1304GlyfsTer11 frameshift_variant De novo - Simplex 37196654 Rots D et al. (2023)
c.1039C>T p.His347Tyr missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.1120G>A p.Val374Ile missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.2171C>T p.Pro724Leu missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.1085_1088del p.Glu362AlafsTer124 frameshift_variant De novo - - 31124279 Stolerman ES , et al. (2019)
c.3862_3865del p.Phe1288ArgfsTer60 frameshift_variant De novo - - 31124279 Stolerman ES , et al. (2019)
c.1416_1417del p.Cys473SerfsTer36 frameshift_variant Familial Paternal - 37196654 Rots D et al. (2023)
c.3288_3291del p.Ser1096ArgfsTer7 frameshift_variant Unknown - Multiplex 37196654 Rots D et al. (2023)
c.3532C>T p.Arg1178Trp missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.3626G>A p.Arg1209Gln missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.4571A>T p.Thr1524Met missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.4795del p.Leu1599TrpfsTer39 frameshift_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.654_655del p.Glu220GlyfsTer16 frameshift_variant Familial Maternal Unknown 37196654 Rots D et al. (2023)
c.1018del p.Arg340AlafsTer147 frameshift_variant Familial Maternal Multiplex 37196654 Rots D et al. (2023)
c.3251_3261delinsCCAG p.Val1084AlafsTer5 frameshift_variant De novo - - 31124279 Stolerman ES , et al. (2019)
c.4184_4186del p.Asn1395_Phe1396delinsIle inframe_deletion De novo - Simplex 25363768 Iossifov I et al. (2014)
c.1085_1088del p.Glu362AlafsTer124 frameshift_variant Familial Maternal Multiplex 37196654 Rots D et al. (2023)
c.1085_1088del p.Glu362AlafsTer124 frameshift_variant Familial Paternal Multiplex 37196654 Rots D et al. (2023)
c.1053_1056del p.Ala352ProfsTer134 frameshift_variant Unknown Not maternal Simplex 37196654 Rots D et al. (2023)
c.2985_2988delinsGGGACAGTGCC p.Arg996GlyfsTer7 frameshift_variant De novo - Simplex 37196654 Rots D et al. (2023)
c.4020_4021delinsAT p.Trp1340_Lys1341delinsTer frameshift_variant Unknown - Multiplex 37196654 Rots D et al. (2023)
c.1668_1673del p.Asn557_Ser558del inframe_deletion Familial Both parents Multiplex 28097321 Reuter MS , et al. (2017)
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.

1/1/2020
1
icon
1

Score remained at 1

Description

Two de novo LoF variants in the KDM6B gene (one frameshift, one splice-site) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768).

Reports Added
[Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism2020]
10/1/2019
3
icon
1

Decreased from 3 to 1

New Scoring Scheme
Description

Two de novo LoF variants in the KDM6B gene (one frameshift, one splice-site) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768).

Reports Added
[Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes2019] [New Scoring Scheme]
7/1/2019
3
icon
3

Decreased from 3 to 3

Description

Two de novo LoF variants in the KDM6B gene (one frameshift, one splice-site) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768).

Reports Added
[Genetic variants in the KDM6B gene are associated with neurodevelopmental delays and dysmorphic features.2019] [Pathogenicity and functional impact of non-frameshifting insertion/deletion variation in the human genome.2019]
10/1/2017
3
icon
3

Decreased from 3 to 3

Description

Two de novo LoF variants in the KDM6B gene (one frameshift, one splice-site) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768).

Reports Added
[Contribution of rare inherited and de novo variants in 2,871 congenital heart disease probands.2017]
4/1/2017
3
icon
3

Decreased from 3 to 3

Description

Two de novo LoF variants in the KDM6B gene (one frameshift, one splice-site) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768).

Reports Added
[De novo gene disruptions in children on the autistic spectrum.2012] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016] [Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders.2017] [Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder2017]
1/1/2017
3
icon
3

Decreased from 3 to 3

Description

Two de novo LoF variants in the KDM6B gene (one frameshift, one splice-site) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768).

Reports Added
[Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders.2017]
7/1/2016
3
icon
3

Decreased from 3 to 3

Description

Two de novo LoF variants in the KDM6B gene (one frameshift, one splice-site) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768).

Reports Added
[Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016]
1/1/2016
3
icon
3

Decreased from 3 to 3

Description

Two de novo LoF variants in the KDM6B gene (one frameshift, one splice-site) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768).

Reports Added
[De novo gene disruptions in children on the autistic spectrum.2012] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Low load for disruptive mutations in autism genes and their biased transmission.2015]
10/1/2014
icon
3

Increased from to 3

Description

Two de novo LoF variants in the KDM6B gene (one frameshift, one splice-site) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768).

Krishnan Probability Score

Score 0.56737413909039

Ranking 1182/25841 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 0.99999442492111

Ranking 408/18225 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 0.996

Ranking 14/239 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 0.013306460468598

Ranking 30/18665 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 39

Ranking 52/461 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 0.43427469541995

Ranking 1078/20870 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
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
KMT2B Mouse Protein Binding Q6PDK2
WAS Wiskott-Aldrich syndrome protein Human Protein Binding 7454 P42768
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