Human Gene Module / Chromosome 1 / ASH1L

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

Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
8 / 11
Rare Variants / Common Variants
40 / 0
Aliases
ASH1L, ASH11,  KMT2H, ASH1L
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
1q22
Associated Disorders
DD/NDD, ID, EPS, ASD
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).

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).

Reports related to ASH1L (11 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 (autism) and epilepsy/seizures (1/3 cases)
Rare Variants   (40)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.7764_7768dup p.Asp2590AlafsTer7 frameshift_variant De novo - Simplex 24267886 Willsey AJ , et al. (2013)
TTA>T - frameshift_variant De novo - 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.5260A>T p.Ser1754Cys 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.3854C>T p.Pro1285Leu missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.205G>T p.Ala69Ser 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.4361C>G p.Thr1454Arg 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.817A>T p.Lys273Ter stop_gained 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.5260A>T p.Ser1754Cys 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.4478G>A p.Arg1493His 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.3449C>G p.Ala1150Gly missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.431A>G p.Lys144Arg 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.4477C>T p.Arg1493Cys 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.6427G>T p.Glu2143Ter stop_gained De novo - Simplex 25363768 Iossifov I , et al. (2014)
c.7189C>T p.Arg2397Ter stop_gained De novo - - 26325558 Tammimies K , et al. (2015)
delTTTTT p.Lys1347fs frameshift_variant De novo - - 26785492 Homsy J , et al. (2016)
c.6238G>A p.Val2080Ile missense_variant De novo - - 27824329 Wang T , et al. (2016)
c.221C>T p.Ser74Leu missense_variant De novo - - 27824329 Wang T , et al. (2016)
c.221C>T p.Ser74Leu missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.6232G>T p.Val2078Phe missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.6238G>A p.Val2080Ile missense_variant Unknown Not maternal - 27824329 Wang T , et al. (2016)
c.7889G>C p.Arg2630Thr missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.8868_8869delAAinsAAA p.Arg2957LysfsTer19 frameshift_variant De novo - - 28191889 Stessman HA , et al. (2017)
c.7172G>A p.Arg2391His missense_variant Unknown - - 28191889 Stessman HA , et al. (2017)
c.3704_3705delCTinsC p.Glu1236LysfsTer6 frameshift_variant De novo - - 28191889 Stessman HA , et al. (2017)
c.1516_1517del p.Phe506fs frameshift_variant Unknown - Simplex 28263302 C Yuen RK , et al. (2017)
c.8887C>T p.Arg2963Ter stop_gained Unknown - Simplex 28263302 C Yuen RK , et al. (2017)
c.8887C>T p.Arg2963Ter stop_gained Unknown - Simplex 28263302 C Yuen RK , et al. (2017)
c.8356G>A p.Ala2786Pro missense_variant De novo - - 28394464 Okamoto N , et al. (2017)
c.3033delA p.Val1014CysfsTer24 frameshift_variant De novo - - 29276005 Faundes V , et al. (2017)
c.7276C>T p.Arg2426Ter stop_gained De novo - - 29276005 Faundes V , et al. (2017)
- - copy_number_loss De novo - - 29276005 Faundes V , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

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).

Score Delta: Score remained at 1

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.

1/1/2018
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).

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).

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).

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

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

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

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.
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
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
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).
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.
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.
CNVs associated with ASH1L(1 CNVs)
1q22 8 Deletion-Duplication 13  /  34
Animal Models associated with ASH1L(6 Models)
ASH1L_1_KO_HM Genetic
ASH1L_1_KO_HT Genetic
ASH1L_2_KO_HM Genetic
ASH1L_2_KO_HM_IL6_KO_HM RESCUE-Genetic
ASH1L_3_KO_HM Genetic
ASH1L_3_KO_HT Genetic
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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