Gene structure: The KMT2E transcript (NM_182931.3) contains 27 coding exons with a PHD finger domain and a SET domain. Cytogenetic location: 7q22.3. Genomic coordinates (GRCh38): 7:105,014,205-105,115,019.
Pathogenic variants: To date, over 60 pathogenic variants have been reported. No mutational hot spots have been identified. The majority of disease-causing variants are protein truncating, including nonsense, frameshift and splice-disrupting variants. Only ten individuals have been reported with missense variants and several of these individuals appear to be more severely affected with microcephaly and seizures, compared to those with null pathogenic variants.
Normal gene product: The KMT2E gene encodes a catalytically inactive histone methyltransferase protein, and functions as a transcriptional regulator in diverse biological processes in mouse models and functional studies, including cell-cycle progression, maintenance of genomic stability, adult hematopoiesis, and spermatogenesis. KMT2E is ubiquitously expressed in most tissues, including in the developing fetal brain.
Abnormal gene product: Haploinsufficiency is the likely disease mechanism for individuals with protein truncating variants, although this has not been confirmed. Some individuals with missense variants presented with a more severe phenotype suggesting an alternate mechanism such as gain-of-abnormal function or dominant negative. The molecular mechanism of how disruption of KMT2E results in a neurodevelopmental condition is currently not well-understood.
KMT2E