Relevance to Autism

Maroni et al., 2025 identified a cohort of 16 individuals through collaborating clinicians and GeneMatcher with monoallelic DOT1L variants presenting with a variable neurodevelopmental disorder characterized by language delay (13/16), motor delay (9/16), intellectual disability (4/16), a diagnosis of ASD (4/16), seizures/epilepsy (3/16), and craniofacial anomalies (14/16); additional functional studies in this report identified patient-specific missense variants with either decreased (the newly identified p.Asp157Asn variant) or increased (the previously reported p.Glu123Lys variant) methyltransferase activity, while heterozygous forebrain-specific Dot1l conditional knockout mice demonstrated altered early vocalization development in both male and female pups, as well as a sex-specific sociability deficit in the three-chamber test in female Dot1l cKO mice. A previous study (Nil et al., 2023) had reported 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 presenting with some degree of global developmental delay/intellectual disability and at least one major congenital anomaly in most individuals; subsequent functional assessment of DOT1L missense variants in Drosophila and human cells in this report demonstrated gain-of-function effects in flies and increased H3K79 methylation levels in flies and human cells. A number of de novo DOT1L variants, including two de novo loss-of-function variants in probands from the Simons Simplex Collection, have been reported in ASD probands (Iossifov et al., 2014; Satterstrom et al., 2020; Zhou et al., 2022; Fu et al., 2022).

Molecular Function

The protein encoded by this gene is a histone methyltransferase that methylates lysine-79 of histone H3. It is inactive against free core histones, but shows significant histone methyltransferase activity against nucleosomes.

External Links

References