KMT2E (lysine methyltransferase 2E) is a member of the MLL/KMT2 family that plays critical roles in gene expression regulation and neurodevelopment, though it appears to lack intrinsic histone methyltransferase activity 1. The protein functions in diverse biological processes including cell cycle progression, genomic stability maintenance, and embryonic development 1. KMT2E operates through epigenetic mechanisms, with KMT2E-AS1 (its antisense lncRNA) stabilizing KMT2E protein to increase histone H3K4me3 methylation, particularly in hypoxic conditions 2. Functionally, KMT2E haploinsufficiency causes autism-like behaviors and amygdala neuronal development dysfunction in mice, with decreased amygdala metabolism and altered neuronal morphology 3. Heterozygous KMT2E variants cause O'Donnell-Luria-Rodan (ODLURO) syndrome, a neurodevelopmental disorder characterized by intellectual disability, autism, epilepsy, hypotonia, and macrocephaly 45. Most pathogenic variants are de novo protein-truncating mutations, though missense variants cause more severe phenotypes with treatment-resistant epileptic encephalopathy 4. Interestingly, incomplete penetrance has been observed, with pathogenic variants sometimes inherited from asymptomatic parents 6. KMT2E also plays roles in cancer, where it contributes to oxaliplatin resistance in esophageal cancer through APOC1 upregulation 7.