Relevance to Autism

This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (Talkowski et al., 2012); this BCA-disrupted gene was also individually implicated by case-control CNV burden or by a minimum of 3 CNVs in neuodevelopmental disorder (NDD) cases with none in controls in a follow-up study in the same report. Disruptions in the EHMT1 gene are the cause of Kleefstra syndrome, which is accompanied by autistic features and intellectual disability (PMIDs 15805155, 16826528, 19264732). This gene was identified as an ASD candidate gene following the identification of a balanced chromosomal abnormality (BCA) leading to gene disruption in an ASD case (PMID 22521361). This report also showed significant burden (P=10[-7]) of EHMT1 CNVs in individuals with neurodevelopmental disorder (NDD; ~25% of cases with ASD). Formal evaluation of patients with Kleefstra syndrome with the Social Communication Questionnaire (SCQ) in PMID 26808425 indicated that all patients exceeded the cut-off value, suggesting the presence of possible ASD. Five de novo loss-of-function variants and several potentially damaging missense variants in the EHMT1 gene were reported in ASD probands from the Autism Sequencing Consortium, the MSSNG cohort, and the SPARK cohort in Zhou et al., 2022; 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 this report identified EHMT1 as a gene reaching study-wide significance based on 5,754 constraint genes (P < 8.69E-06).

Molecular Function

The protein encoded by this gene is a histone methyltransferase that is part of the E2F6 complex, which represses transcription. This protein may be involved in the silencing of MYC- and E2F-responsive genes and therefore could play a role in the G0/G1 cell cycle transition. Defects in this gene are a cause of chromosome 9q subtelomeric deletion syndrome (9q-syndrome).

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Model Summary

G9a mutant flies show reduced dendrite development in multidendrite (md) neurons, a decrease in the number of synaptic terminal boutons, increased circling locomotory behavior and misregulation of gene expression. G9a is required in the mushroom body for short term memory. Pan-neuronal G9a knockdown in fly heads leads to gene misregulation, including the Drosophila ortholog of Arc (Arc1).

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