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 / 10
Rare Variants / Common Variants
37 / 0
Aliases
ASH1L, ASH11,  KMT2H, Ã‚ ASH1L
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation
Chromosome Band
1q22
Associated Disorders
ID, DD/NDD, ASD
Relevance to Autism

Two de novo loss-of-function variants in the ASH1L gene have been identified in ASD probands from the Simons Simplex Collection (Iossifov et al., 2014). This gene was also identified in an ASD whole-exome sequencing study and subsequent TADA (transmission and de novo association) analysis as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of <0.1 (De Rubeis et al., 2014).

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 (10 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
Rare Variants   (37)
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 - 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)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

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

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.

04-01-2017
1

Initial score established: 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).

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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