Publication
Heterozygous variants in KMT2E cause a spectrum of neurodevelopmental disorders and epilepsy
Publisher:
Cold Spring Harbor Laboratory
Date:
05-03-2019
DOI:
10.1101/566091
Abstract: We delineate a KMT2E gene-related neurodevelopmental disorder based on 38 in iduals in 36 families. This includes 31 distinct heterozygous variants in the KMT2E gene (28 ascertained from Matchmaker Exchange and 3 previously reported), and 4 in iduals with chromosome 7q22.2-22.23 microdeletions encompassing the KMT2E gene (1 previously reported). Almost all variants occurred de novo, and most were truncating. Most affected in iduals with protein-truncating variants presented with mild intellectual disability. One-quarter of in iduals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of in iduals with truncating variants, and was responsive to treatment with anti-epileptic medications in almost all. Over 70% of the in iduals were male and expressivity was variable by sex, with epilepsy more common in females and autism more common in males. The four in iduals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four in iduals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all in iduals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant negative effects specific to these missense variants in KMT2E may explain this ergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.