Publication Date
11-2-2023
Journal
The American Journal of Human Genetics
DOI
10.1016/j.ajhg.2023.09.009
PMID
37827158
PMCID
PMC10645550
PubMedCentral® Posted Date
10-11-2023
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Humans, Congenital Abnormalities, Developmental Disabilities, Drosophila, Drosophila Proteins, Gain of Function Mutation, Histone-Lysine N-Methyltransferase, Histones, Lysine, Methylation, Methyltransferases, Neoplasms, DOT1 Like histone lysine methyltransferase, DOT1L, histone lysine methyltransferase, H3K79 methylation, Drosophila, grappa, gpp, gain of function, developmental delay, congenital anomalies
Abstract
Misregulation of histone lysine methylation is associated with several human cancers and with human developmental disorders. DOT1L is an evolutionarily conserved gene encoding a lysine methyltransferase (KMT) that methylates histone 3 lysine-79 (H3K79) and was not previously associated with a Mendelian disease in OMIM. We have identified nine unrelated individuals with seven different de novo heterozygous missense variants in DOT1L through the Undiagnosed Disease Network (UDN), the SickKids Complex Care genomics project, and GeneMatcher. All probands had some degree of global developmental delay/intellectual disability, and most had one or more major congenital anomalies. To assess the pathogenicity of the DOT1L variants, functional studies were performed in Drosophila and human cells. The fruit fly DOT1L ortholog, grappa, is expressed in most cells including neurons in the central nervous system. The identified DOT1L variants behave as gain-of-function alleles in flies and lead to increased H3K79 methylation levels in flies and human cells. Our results show that human DOT1L and fly grappa are required for proper development and that de novo heterozygous variants in DOT1L are associated with a Mendelian disease.
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