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Background  Histone H3 methylation at lysine 9 (H3K9) is a conserved epigenetic signal, mediating heterochromatin formation by trimethylation, and transcriptional silencing by dimethylation. Defective GLP ( Ehmt1 ) and G9a ( Ehmt2 ) histone lysine methyltransferases, involved in mono and dimethylation of H3K9, confer autistic phenotypes and behavioral abnormalities in animal models. Moreover,  EHMT1  loss of function results in Kleefstra syndrome, characterized by severe intellectual disability, developmental delays and psychiatric disorders. We examined the possible role of histone methyltransferases in the etiology of autism spectrum disorders (ASD) and suggest that rare functional variants in these genes that regulate H3K9 methylation may be associated with ASD.    Methods  Since G9a-GLP-Wiz forms a heteromeric methyltransferase complex, all the protein-coding regions and exon/intron boundaries of  EHMT1, EHMT2  and  WIZ  were sequenced in Japanese ASD subjects. The detected variants were prioritized based on novelty and functionality. The expression levels of these genes were tested in blood cells and postmortem brain samples from ASD and control subjects. Expression of  EHMT1  and  EHMT2  isoforms were determined by digital PCR.    Results  We identified six nonsynonymous variants: three in  EHMT1 , two in  EHMT2  and one in  WIZ . Two variants, the  EHMT1  ankyrin repeat domain (Lys968Arg) and  EHMT2  SET domain (Thr961Ile) variants were present exclusively in cases, but showed no statistically significant association with ASD. The  EHMT2  transcript expression was significantly elevated in the peripheral blood cells of ASD when compared with control samples; but not for  EHMT1  and  WIZ . Gene expression levels of  EHMT1, EHMT2  and  WIZ  in Brodmann area (BA) 9, BA21, BA40 and the dorsal raphe nucleus (DoRN) regions from postmortem brain samples showed no significant changes between ASD and control subjects. Nor did expression levels of  EHMT1  and  EHMT2  isoforms in the prefrontal cortex differ significantly between ASD and control groups.    Conclusions  We identified two novel rare missense variants in the  EHMT1  and  EHMT2  genes of ASD patients. We surmise that these variants alone may not be sufficient to exert a significant effect on ASD pathogenesis. The elevated expression of  EHMT2  in the peripheral blood cells may support the notion of a restrictive chromatin state in ASD, similar to schizophrenia.    Electronic supplementary material  The online version of this article (doi:10.1186/2040-2392-5-49) contains supplementary material, which is available to authorized users.

Exon resequencing of H3K9 methyltransferase complex genes, EHMT1, EHTM2 and WIZ, in Japanese autism subjects