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).

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References

Model Summary

ash1-VDRC108832 mutants' initial jump response was impaired. Ash1-VDRC28982 mutants showed no change in habituation.

References