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Kleefstra syndrome, caused by haploinsufficiency of  euchromatin histone methyltransferase 1  ( EHMT1 ), is characterized by intellectual disability (ID), autism spectrum disorder (ASD), characteristic facial dysmorphisms, and other variable clinical features. In addition to  EHMT1  mutations,  de novo  variants were reported in four additional genes ( MBD5 ,  SMARCB1 ,  NR1I3 , and  KMT2C ), in single individuals with clinical characteristics overlapping Kleefstra syndrome. Here, we present a novel cohort of five patients with  de novo  loss of function mutations affecting the histone methyltransferase KMT2C. Our clinical data delineates the  KMT2C  phenotypic spectrum and reinforces the phenotypic overlap with Kleefstra syndrome and other related ID disorders. To elucidate the common molecular basis of the neuropathology associated with mutations in  KMT2C  and  EHMT1 , we characterized the role of the  Drosophila  KMT2C ortholog, trithorax related (trr), in the nervous system. Similar to the  Drosophila  EHMT1 ortholog, G9a, trr is required in the mushroom body for short term memory. Trr ChIP-seq identified 3371 binding sites, mainly in the promoter of genes involved in neuronal processes. Transcriptional profiling of pan-neuronal  trr  knockdown and  G9a  null mutant fly heads identified 613 and 1123 misregulated genes, respectively. These gene sets show a significant overlap and are associated with nearly identical gene ontology enrichments. The majority of the observed biological convergence is derived from predicted indirect target genes. However, trr and G9a also have common direct targets, including the  Drosophila  ortholog of Arc (Arc1), a key regulator of synaptic plasticity. Our data highlight the clinical and molecular convergence between the KMT2 and EHMT protein families, which may contribute to a molecular network underlying a larger group of ID/ASD-related disorders.

Functional convergence of histone methyltransferases EHMT1 and KMT2C involved in intellectual disability and autism spectrum disorder