Human Gene Module / Chromosome 1 / ASH1L

ASH1LAsh1 (absent, small, or homeotic)-like (Drosophila)

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
24 / 34
Rare Variants / Common Variants
131 / 2
EAGLE Score
14.15
Strong Learn More
Aliases
ASH1L, ASH11,  KMT2H, ASH1L
Associated Syndromes
Tourette syndrome
Chromosome Band
1q22
Associated Disorders
DD/NDD, ID, ASD, EPS
Genetic Category
Rare Single Gene Mutation, Syndromic, Genetic Association, Functional
Relevance to Autism

Two de novo loss-of-function (LoF) variants in the ASH1L gene were identified in ASD probands from the Simons Simplex Collection (PMIDs 24267886, 25363768), while a third de novo LoF variant in this gene was identified in one ASD proband from 2,270 trios screened by the Autism Sequencing Consortium in De Rubeis et al., 2014 (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in this report identified ASH1L as a gene meeting high statistical significance with a 0.05 < FDR 0.1, meaning that this gene had a 90% chance of being a true autism gene. A fourth de novo LoF variant in the ASH1L gene was identified in an ASD proband in Tammimies et al., 2015 (PMID 26325558). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). An additional de novo LoF variant in ASH1L was identifed in a proband from the Pediatric Cardiac Genetics Consortium who presented with ASD, developmental delay, and intellectual disability in addition to congenital heart disease (Homsy et al., 2015). De novo and inherited missense variants that were predicted to be deleterious were identified in ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort in (PMID 27824329). De novo LoF variants in ASH1L have also been identified in individuals with intellectual disability in Stessman et al., 2017 (PMID 28191889) and Okamoto et al., 2017 (PMID 28394464). 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 ASH1L as a gene reaching exome-wide significance (P < 2.5E-06).

Molecular Function

This gene encodes a member of the trithorax group of transcriptional activators. The encoded product functions as a histone methyltransferase specifically methylating 'Lys-36' of histone H3 (H3K36me).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
Fruit fly
Entrez Gene
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to ASH1L (34 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism Willsey AJ , et al. (2013) 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 Support Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder Tammimies K , et al. (2015) Yes -
5 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission Iossifov I , et al. (2015) Yes -
6 Recent Recommendation De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies Homsy J , et al. (2016) No ASD, DD, ID
7 Support De novo genic mutations among a Chinese autism spectrum disorder cohort Wang T , et al. (2016) Yes -
8 Recent Recommendation Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases Stessman HA , et al. (2017) Yes -
9 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
10 Support Novel MCA/ID syndrome with ASH1L mutation Okamoto N , et al. (2017) No Microcephaly, dysmorphic features, MCA
11 Support Histone Lysine Methylases and Demethylases in the Landscape of Human Developmental Disorders Faundes V , et al. (2017) No ASD, epilepsy/seizures
12 Support De novo loss-of-function variants of ASH1L are associated with an emergent neurodevelopmental disorder Shen W , et al. (2018) No -
13 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model Guo H , et al. (2018) Yes -
14 Support Characterization of intellectual disability and autism comorbidity through gene panel sequencing Aspromonte MC , et al. (2019) Yes -
15 Recent Recommendation Mutations in ASH1L confer susceptibility to Tourette syndrome Liu S , et al. (2019) No -
16 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
17 Support Phenotypic and genetic spectrum of epilepsy with myoclonic atonic seizures Tang S et al. (2020) Yes -
18 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes -
19 Support - Gao Y et al. (2021) Yes -
20 Support - Dhaliwal J et al. (2021) Yes -
21 Support - Mitani T et al. (2021) No -
22 Support - Qin L et al. (2021) Yes Epilepsy/seizures
23 Support - Li D et al. (2022) Yes -
24 Recent Recommendation - Yan Y et al. (2022) Yes -
25 Support - Cheon S et al. (2022) No -
26 Positive Association - Liu W et al. (2022) No -
27 Support - Singh T et al. (2022) No -
28 Support - Gao Y et al. (2022) Yes -
29 Support - Zhou X et al. (2022) Yes -
30 Support - Hu C et al. (2023) Yes -
31 Support - Zhang Y et al. (2023) Yes ID
32 Support - Sanchis-Juan A et al. (2023) No -
33 Support - Sheth F et al. (2023) Yes DD, ID
34 Support - et al. () Yes OCD, ID, epilepsy/seizures
Rare Variants   (131)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - - 29276005 Faundes V , et al. (2017)
c.420+2T>C - splice_site_variant Unknown - - 33004838 Wang T et al. (2020)
c.6009-2A>G - splice_site_variant Unknown - - 31673123 Liu S , et al. (2019)
c.1348C>T p.Gln450Ter stop_gained De novo - - 33004838 Wang T et al. (2020)
c.4024C>T p.Arg1342Ter stop_gained De novo - - 32469098 Tang S et al. (2020)
c.7204C>T p.Arg2402Ter stop_gained De novo - - 33004838 Wang T et al. (2020)
c.7618C>T p.Arg2540Ter stop_gained De novo - - 33004838 Wang T et al. (2020)
c.8902C>T p.Arg2968Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.6238+3G>C - splice_region_variant De novo - - 35982159 Zhou X et al. (2022)
c.46G>A p.Glu16Lys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.221C>T p.Ser74Leu missense_variant Unknown - - 31673123 Liu S , et al. (2019)
c.221C>T p.Ser74Leu missense_variant De novo - - 27824329 Wang T , et al. (2016)
c.1318T>G p.Cys440Gly missense_variant Unknown - - 31673123 Liu S , et al. (2019)
c.1518C>G p.Phe506Leu missense_variant Unknown - - 31673123 Liu S , et al. (2019)
c.1673C>T p.Pro558Leu missense_variant Unknown - - 31673123 Liu S , et al. (2019)
c.7276C>T p.Arg2426Ter stop_gained De novo - - 29276005 Faundes V , et al. (2017)
c.4546C>T p.Arg1516Cys missense_variant Unknown - - 31673123 Liu S , et al. (2019)
c.4583A>G p.Tyr1528Cys missense_variant Unknown - - 31673123 Liu S , et al. (2019)
c.5158C>T p.Arg1720Trp missense_variant Unknown - - 31673123 Liu S , et al. (2019)
c.5384T>C p.Ile1795Thr missense_variant Unknown - - 31673123 Liu S , et al. (2019)
c.5744A>G p.Lys1915Arg missense_variant Unknown - - 31673123 Liu S , et al. (2019)
c.6598A>G p.Ser2200Gly missense_variant Unknown - - 31673123 Liu S , et al. (2019)
c.7502A>G p.Lys2501Arg missense_variant Unknown - - 31673123 Liu S , et al. (2019)
c.7916A>C p.His2639Pro missense_variant Unknown - - 31673123 Liu S , et al. (2019)
c.7975C>T p.Arg2659Cys missense_variant Unknown - - 31673123 Liu S , et al. (2019)
c.3760C>T p.Arg1254Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3904C>T p.Arg1302Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3905G>A p.Arg1302Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3905G>C p.Arg1302Pro missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4604G>T p.Arg1535Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4870C>T p.Arg1624Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.5050C>T p.Arg1684Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.5051G>A p.Arg1684Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.5422C>T p.Arg1808Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.6007G>A p.Asp2003Asn missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.6868C>T p.Arg2290Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.6869G>A p.Arg2290His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.6931C>T p.Arg2311Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.7187G>A p.Arg2396His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.7286G>A p.Arg2429Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.7313A>G p.Glu2438Gly missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.7558C>T p.Arg2520Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.7598G>A p.Arg2533His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.7598G>A p.Gly2533Glu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.7619G>A p.Arg2540Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.7637C>T p.Ala2546Val missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.7640G>A p.Arg2547Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.7759C>T p.Arg2587Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.8030G>A p.Arg2677His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.8201G>A p.Arg2734His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.8429C>T p.Ala2810Val missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.8459C>T p.Ser2820Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.8482T>C p.Tyr2828His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.8536C>T p.Arg2846Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.8764G>A p.Glu2922Lys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3515C>T p.Ser1172Leu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.6238G>A p.Val2080Ile missense_variant De novo - - 27824329 Wang T , et al. (2016)
c.7189C>T p.Arg2397Ter stop_gained De novo - - 26325558 Tammimies K , et al. (2015)
c.3567dup p.Glu1190Ter frameshift_variant De novo - - 33004838 Wang T et al. (2020)
c.102G>C p.Lys34Asn missense_variant Familial Paternal - 37007974 Hu C et al. (2023)
c.8356G>A p.Ala2786Thr missense_variant De novo - - 28394464 Okamoto N , et al. (2017)
c.8887C>T p.Arg2963Ter stop_gained Unknown - Simplex 28263302 C Yuen RK et al. (2017)
c.3771T>G p.His1257Gln missense_variant Familial Paternal Simplex 38256266 et al. ()
c.6427G>T p.Glu2143Ter stop_gained De novo - Simplex 25363768 Iossifov I et al. (2014)
c.7172G>A p.Arg2391His missense_variant Unknown - - 28191889 Stessman HA , et al. (2017)
c.817A>T p.Lys273Ter stop_gained De novo - Unknown 25363760 De Rubeis S , et al. (2014)
c.921dup p.Leu308ThrfsTer11 frameshift_variant De novo - - 33004838 Wang T et al. (2020)
c.5744A>G p.Lys1915Arg missense_variant De novo - Simplex 30564305 Guo H , et al. (2018)
c.4639A>G p.Lys1547Glu missense_variant De novo - Simplex 31673123 Liu S , et al. (2019)
c.3760C>T p.Arg1254Cys missense_variant Unknown - Simplex 33004838 Wang T et al. (2020)
c.221C>T p.Ser74Leu missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.2134dup p.Arg712LysfsTer10 frameshift_variant Unknown - - 31673123 Liu S , et al. (2019)
c.3681del p.Phe1227LeufsTer6 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.8698dup p.Thr2900AsnfsTer5 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.3319A>G p.Ile1107Val missense_variant De novo - - 31209962 Aspromonte MC , et al. (2019)
c.4025G>A p.Arg1342Gln missense_variant Familial Paternal - 33004838 Wang T et al. (2020)
c.4546C>T p.Arg1516Cys missense_variant Familial Paternal - 33004838 Wang T et al. (2020)
c.6169C>G p.His2057Asp missense_variant Familial Paternal - 33004838 Wang T et al. (2020)
c.6931C>T p.Arg2311Trp missense_variant Familial Paternal - 33004838 Wang T et al. (2020)
c.5446dup p.Ile1816AsnfsTer13 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.6247del p.Leu2083PhefsTer30 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.8698del p.Thr2900GlnfsTer44 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.8595del p.Glu2866ArgfsTer3 frameshift_variant De novo - - 37035742 Zhang Y et al. (2023)
c.1577dup p.Tyr526Ter stop_gained Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.6232G>T p.Val2078Phe missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.7889G>C p.Arg2630Thr missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.431A>G p.Lys144Arg missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.7760G>A p.Arg2587His missense_variant Unknown Not maternal - 33004838 Wang T et al. (2020)
c.8854_8855insT p.Gly2952ValfsTer24 frameshift_variant Unknown - - 34968013 Li D et al. (2022)
c.4039_4043del p.Lys1347GlufsTer7 frameshift_variant De novo - - 33004838 Wang T et al. (2020)
c.221C>T p.Ser74Leu missense_variant Familial Maternal Simplex 31673123 Liu S , et al. (2019)
c.6238G>A p.Val2080Ile missense_variant Unknown Not maternal - 27824329 Wang T , et al. (2016)
c.3033del p.Val1014CysfsTer24 frameshift_variant De novo - - 29276005 Faundes V , et al. (2017)
c.3449C>G p.Ala1150Gly missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.4008C>A p.Asp1336Glu missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.4456C>T p.Arg1486Cys missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.4477C>T p.Arg1493Cys missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.4478G>A p.Arg1493His missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.4927C>T p.Arg1643Trp missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.5260A>T p.Ser1754Cys missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.7094A>G p.Asn2365Ser missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.8747G>A p.Arg2916Gln missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.4651_4654del p.Asn1551GlufsTer60 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.1958dup p.Pro654AlafsTer6 frameshift_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.229G>A p.Glu77Lys missense_variant Familial Paternal Simplex 37543562 Sheth F et al. (2023)
c.3704del p.Pro1235LeufsTer7 frameshift_variant De novo - - 28191889 Stessman HA , et al. (2017)
c.773del p.Gly258ValfsTer5 frameshift_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.4046_4050del p.Lys1349ArgfsTer5 frameshift_variant De novo - - 26785492 Homsy J , et al. (2016)
c.8869dup p.Ile2957AsnfsTer14 frameshift_variant De novo - - 28191889 Stessman HA , et al. (2017)
c.5831T>G p.Phe1944Cys missense_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.8342G>A p.Arg2781Gln missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.4546C>T p.Arg1516Cys missense_variant Familial Paternal Simplex 31673123 Liu S , et al. (2019)
c.6230A>T p.Tyr2077Phe missense_variant Familial Maternal Simplex 31673123 Liu S , et al. (2019)
c.7889G>C p.Arg2630Thr missense_variant Familial Paternal Simplex 31673123 Liu S , et al. (2019)
c.2422_2423delinsT p.Lys808TyrfsTer40 frameshift_variant De novo - - 29753921 Shen W , et al. (2018)
c.205G>T p.Ala69Ser missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.2309_2310insCATGATCTACAAATGA p.Asp771MetfsTer5 stop_gained Unknown - - 31673123 Liu S , et al. (2019)
c.4902_4903del p.Ser1635CysfsTer18 frameshift_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1298A>C p.Gln433Pro missense_variant Familial Maternal Multiplex 34356069 Dhaliwal J et al. (2021)
c.4025G>A p.Arg1342Gln missense_variant Familial Both parents Simplex 34582790 Mitani T et al. (2021)
c.1516_1517del p.Phe506LeufsTer4 frameshift_variant Unknown - Simplex 28263302 C Yuen RK et al. (2017)
c.3854C>T p.Pro1285Leu missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.3857A>T p.Asp1286Val missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.4361C>G p.Thr1454Arg missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.5260A>T p.Ser1754Cys missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.5260A>T p.Ser1754Cys missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.7598G>A p.Arg2533His missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.8375T>G p.Ile2792Ser missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.5081dup p.Thr1695AsnfsTer18 frameshift_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.3744_3745del p.His1248GlnfsTer5 frameshift_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.7764_7765insCAAGG p.Lys2589GlnfsTer8 frameshift_variant De novo - Simplex 24267886 Willsey AJ , et al. (2013)
Common Variants   (2)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.-99-9605A>G - intron_variant - - - 35307981 Liu W et al. (2022)
c.6332+3029T>C - intron_variant - - - 35307981 Liu W et al. (2022)
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.

10/1/2020
1
icon
1

Score remained at 1

Description

Two de novo loss-of-function (LoF) variants in the ASH1L gene were identified in ASD probands from the Simons Simplex Collection (PMIDs 24267886, 25363768), while a third de novo LoF variant in this gene was identified in one ASD proband from 2,270 trios screened by the Autism Sequencing Consortium in De Rubeis et al., 2014 (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in this report identified ASH1L as a gene meeting high statistical significance with a 0.05 < FDR 0.1, meaning that this gene had a 90% chance of being a true autism gene. A fourth de novo LoF variant in the ASH1L gene was identified in an ASD proband in Tammimies et al., 2015 (PMID 26325558). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). An additional de novo LoF variant in ASH1L was identifed in a proband from the Pediatric Cardiac Genetics Consortium who presented with ASD, developmental delay, and intellectual disability in addition to congenital heart disease (Homsy et al., 2015). De novo and inherited missense variants that were predicted to be deleterious were identified in ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort in (PMID 27824329). De novo LoF variants in ASH1L have also been identified in individuals with intellectual disability in Stessman et al., 2017 (PMID 28191889) and Okamoto et al., 2017 (PMID 28394464). Whole-exome sequencing of 100 Chinese Tourette syndrome (TS) trios in Liu et al., 2019 identified ASH1L as a risk gene that was both de novo mutated and associated with TS based on a transmission disequilibrium test; follow-up targeted sequencing in a replication cohort of 524 unrelated TS samples replicated association of ASH1L with Tourette syndrome (P-value 0.001). Ash1l +/- mice were also shown to exhibit tic-like and compulsive behaviors that could be rescued by the tic-relieving drug haloperidol in Liu et al., 2019.

Reports Added
[Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders2020]
4/1/2020
1
icon
1

Score remained at 1

Description

Two de novo loss-of-function (LoF) variants in the ASH1L gene were identified in ASD probands from the Simons Simplex Collection (PMIDs 24267886, 25363768), while a third de novo LoF variant in this gene was identified in one ASD proband from 2,270 trios screened by the Autism Sequencing Consortium in De Rubeis et al., 2014 (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in this report identified ASH1L as a gene meeting high statistical significance with a 0.05 < FDR 0.1, meaning that this gene had a 90% chance of being a true autism gene. A fourth de novo LoF variant in the ASH1L gene was identified in an ASD proband in Tammimies et al., 2015 (PMID 26325558). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). An additional de novo LoF variant in ASH1L was identifed in a proband from the Pediatric Cardiac Genetics Consortium who presented with ASD, developmental delay, and intellectual disability in addition to congenital heart disease (Homsy et al., 2015). De novo and inherited missense variants that were predicted to be deleterious were identified in ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort in (PMID 27824329). De novo LoF variants in ASH1L have also been identified in individuals with intellectual disability in Stessman et al., 2017 (PMID 28191889) and Okamoto et al., 2017 (PMID 28394464). Whole-exome sequencing of 100 Chinese Tourette syndrome (TS) trios in Liu et al., 2019 identified ASH1L as a risk gene that was both de novo mutated and associated with TS based on a transmission disequilibrium test; follow-up targeted sequencing in a replication cohort of 524 unrelated TS samples replicated association of ASH1L with Tourette syndrome (P-value 0.001). Ash1l +/- mice were also shown to exhibit tic-like and compulsive behaviors that could be rescued by the tic-relieving drug haloperidol in Liu et al., 2019.

Reports Added
[Phenotypic and genetic spectrum of epilepsy with myoclonic atonic seizures2020]
1/1/2020
1
icon
1

Score remained at 1

Description

Two de novo loss-of-function (LoF) variants in the ASH1L gene were identified in ASD probands from the Simons Simplex Collection (PMIDs 24267886, 25363768), while a third de novo LoF variant in this gene was identified in one ASD proband from 2,270 trios screened by the Autism Sequencing Consortium in De Rubeis et al., 2014 (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in this report identified ASH1L as a gene meeting high statistical significance with a 0.05 < FDR 0.1, meaning that this gene had a 90% chance of being a true autism gene. A fourth de novo LoF variant in the ASH1L gene was identified in an ASD proband in Tammimies et al., 2015 (PMID 26325558). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). An additional de novo LoF variant in ASH1L was identifed in a proband from the Pediatric Cardiac Genetics Consortium who presented with ASD, developmental delay, and intellectual disability in addition to congenital heart disease (Homsy et al., 2015). De novo and inherited missense variants that were predicted to be deleterious were identified in ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort in (PMID 27824329). De novo LoF variants in ASH1L have also been identified in individuals with intellectual disability in Stessman et al., 2017 (PMID 28191889) and Okamoto et al., 2017 (PMID 28394464). Whole-exome sequencing of 100 Chinese Tourette syndrome (TS) trios in Liu et al., 2019 identified ASH1L as a risk gene that was both de novo mutated and associated with TS based on a transmission disequilibrium test; follow-up targeted sequencing in a replication cohort of 524 unrelated TS samples replicated association of ASH1L with Tourette syndrome (P-value 0.001). Ash1l +/- mice were also shown to exhibit tic-like and compulsive behaviors that could be rescued by the tic-relieving drug haloperidol in Liu et al., 2019.

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

Score remained at 1

New Scoring Scheme
Description

Two de novo loss-of-function (LoF) variants in the ASH1L gene were identified in ASD probands from the Simons Simplex Collection (PMIDs 24267886, 25363768), while a third de novo LoF variant in this gene was identified in one ASD proband from 2,270 trios screened by the Autism Sequencing Consortium in De Rubeis et al., 2014 (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in this report identified ASH1L as a gene meeting high statistical significance with a 0.05 < FDR 0.1, meaning that this gene had a 90% chance of being a true autism gene. A fourth de novo LoF variant in the ASH1L gene was identified in an ASD proband in Tammimies et al., 2015 (PMID 26325558). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). An additional de novo LoF variant in ASH1L was identifed in a proband from the Pediatric Cardiac Genetics Consortium who presented with ASD, developmental delay, and intellectual disability in addition to congenital heart disease (Homsy et al., 2015). De novo and inherited missense variants that were predicted to be deleterious were identified in ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort in (PMID 27824329). De novo LoF variants in ASH1L have also been identified in individuals with intellectual disability in Stessman et al., 2017 (PMID 28191889) and Okamoto et al., 2017 (PMID 28394464). Whole-exome sequencing of 100 Chinese Tourette syndrome (TS) trios in Liu et al., 2019 identified ASH1L as a risk gene that was both de novo mutated and associated with TS based on a transmission disequilibrium test; follow-up targeted sequencing in a replication cohort of 524 unrelated TS samples replicated association of ASH1L with Tourette syndrome (P-value 0.001). Ash1l +/- mice were also shown to exhibit tic-like and compulsive behaviors that could be rescued by the tic-relieving drug haloperidol in Liu et al., 2019.

Reports Added
[Mutations in ASH1L confer susceptibility to Tourette syndrome.2019] [New Scoring Scheme]
7/1/2019
1
icon
1

Score remained at 1

Description

Two de novo loss-of-function (LoF) variants in the ASH1L gene were identified in ASD probands from the Simons Simplex Collection (PMIDs 24267886, 25363768), while a third de novo LoF variant in this gene was identified in one ASD proband from 2,270 trios screened by the Autism Sequencing Consortium in De Rubeis et al., 2014 (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in this report identified ASH1L as a gene meeting high statistical significance with a 0.05 < FDR 0.1, meaning that this gene had a 90% chance of being a true autism gene. A fourth de novo LoF variant in the ASH1L gene was identified in an ASD proband in Tammimies et al., 2015 (PMID 26325558). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). An additional de novo LoF variant in ASH1L was identifed in a proband from the Pediatric Cardiac Genetics Consortium who presented with ASD, developmental delay, and intellectual disability in addition to congenital heart disease (Homsy et al., 2015). De novo and inherited missense variants that were predicted to be deleterious were identified in ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort in (PMID 27824329). De novo LoF variants in ASH1L have also been identified in individuals with intellectual disability in Stessman et al., 2017 (PMID 28191889) and Okamoto et al., 2017 (PMID 28394464).

Reports Added
[Characterization of intellectual disability and autism comorbidity through gene panel sequencing.2019]
1/1/2019
1
icon
1

Score remained at 1

Description

Two de novo loss-of-function (LoF) variants in the ASH1L gene were identified in ASD probands from the Simons Simplex Collection (PMIDs 24267886, 25363768), while a third de novo LoF variant in this gene was identified in one ASD proband from 2,270 trios screened by the Autism Sequencing Consortium in De Rubeis et al., 2014 (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in this report identified ASH1L as a gene meeting high statistical significance with a 0.05 < FDR 0.1, meaning that this gene had a 90% chance of being a true autism gene. A fourth de novo LoF variant in the ASH1L gene was identified in an ASD proband in Tammimies et al., 2015 (PMID 26325558). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). An additional de novo LoF variant in ASH1L was identifed in a proband from the Pediatric Cardiac Genetics Consortium who presented with ASD, developmental delay, and intellectual disability in addition to congenital heart disease (Homsy et al., 2015). De novo and inherited missense variants that were predicted to be deleterious were identified in ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort in (PMID 27824329). De novo LoF variants in ASH1L have also been identified in individuals with intellectual disability in Stessman et al., 2017 (PMID 28191889) and Okamoto et al., 2017 (PMID 28394464).

Reports Added
[Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.2018]
4/1/2017
1
icon
1

Score remained at 1

Description

Two de novo LoF variants in the ASH1L gene were identified in ASD probands from the Simons Simplex Collection (PMIDs 24267886, 25363768), while a third de novo LoF variant in this gene was identified in one ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified ASH1L as a gene meeting high statistical significance with a 0.05< FDR ?0.1, meaning that this gene had a ?90% chance of being a true autism gene (PMID 25363760). A fourth de novo LoF variant in the ASH1L gene was recently identified in an ASD proband in PMID 26325558. This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). A de novo LoF variant in ASH1L was identifed in a proband from the Pediatric Cardiac Genetics Consortium who presented with ASD, developmental delay, and intellectual disability in addition to congenital heart disease (Homsy et al., 2015).

Reports Added
[Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism.2013] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies.2016] [De novo genic mutations among a Chinese autism spectrum disorder cohort.2016] [Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.2017] [Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder2017] [Novel MCA/ID syndrome with ASH1L mutation.2017]
1/1/2017
1
icon
1

Score remained at 1

Description

Two de novo LoF variants in the ASH1L gene were identified in ASD probands from the Simons Simplex Collection (PMIDs 24267886, 25363768), while a third de novo LoF variant in this gene was identified in one ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified ASH1L as a gene meeting high statistical significance with a 0.05 < FDR ?0.1, meaning that this gene had a ?90% chance of being a true autism gene (PMID 25363760). A fourth de novo LoF variant in the ASH1L gene was recently identified in an ASD proband in PMID 26325558. This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). A de novo LoF variant in ASH1L was identifed in a proband from the Pediatric Cardiac Genetics Consortium who presented with ASD, developmental delay, and intellectual disability in addition to congenital heart disease (Homsy et al., 2015).

Reports Added
[Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.2017]
10/1/2016
1
icon
1

Score remained at 1

Description

Two de novo LoF variants in the ASH1L gene were identified in ASD probands from the Simons Simplex Collection (PMIDs 24267886, 25363768), while a third de novo LoF variant in this gene was identified in one ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified ASH1L as a gene meeting high statistical significance with a 0.05

Reports Added
[De novo genic mutations among a Chinese autism spectrum disorder cohort.2016]
1/1/2016
1
icon
1

Score remained at 1

Description

Two de novo LoF variants in the ASH1L gene were identified in ASD probands from the Simons Simplex Collection (PMIDs 24267886, 25363768), while a third de novo LoF variant in this gene was identified in one ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified ASH1L as a gene meeting high statistical significance with a 0.05

Reports Added
[Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism.2013] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [De novo mutations in congenital heart disease with neurodevelopmental and other congenital anomalies.2016]
7/1/2015
1
icon
1

Score remained at 1

Description

Two de novo LoF variants in the ASH1L gene were identified in ASD probands from the Simons Simplex Collection (PMIDs 24267886, 25363768), while a third de novo LoF variant in this gene was identified in one ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified ASH1L as a gene meeting high statistical significance with a 0.05

Reports Added
[Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism.2013] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder.2015]
10/1/2014
icon
1

Increased from to 1

Description

Two de novo LoF variants in the ASH1L gene were identified in ASD probands from the Simons Simplex Collection (PMIDs 24267886, 25363768), while a third de novo LoF variant in this gene was identified in one ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified ASH1L as a gene meeting high statistical significance with a 0.05

Krishnan Probability Score

Score 0.49345042310572

Ranking 4141/25841 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 0.99999999999983

Ranking 29/18225 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 0.998

Ranking 6/239 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 0.0042530785553672

Ranking 24/18665 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 47

Ranking 36/461 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 0.50944372967378

Ranking 448/20870 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
DBET D4Z4 binding element transcript (non-protein coding) Human RNA Binding 100419743
HIST1H3A histone cluster 1, H3a Human Protein Modification 8350 P68431
HOXB6 homeobox B6 Human Direct Regulation 3216 P17509
HOXC8 homeobox C8 Human Direct Regulation NM_022658 P31273
Hoxd4 homeobox D4 Mouse Direct Regulation 15436 P10628
MIR142 microRNA 142 Human RNA Binding 406934
MORF4L1 mortality factor 4 like 1 Human Protein Binding 10933 B7Z6R1
MORF4L2 mortality factor 4 like 2 Human Protein Binding 9643 Q15014
NXF2 Nuclear RNA export factor 2 Human Protein Binding 56001 Q9GZY0
SMAD7 SMAD family member 7 Human Protein Binding 4092 K7EQ10
THAP7 THAP domain containing 7 Human Protein Binding 80764 Q9BT49
Tnfaip3 tumor necrosis factor, alpha-induced protein 3 Mouse Direct Regulation 21929 Q60769
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