Preprint: EHMT1 variants drive severe sleep disruption in Kleefstra syndrome via ROS dysregulation in insulin-producing cells

A preprint posted to bioRxiv on 3 September 2026 presents cross-species evidence that the EHMT1/G9a histone methyltransferase family regulates sleep maintenance, with direct relevance to Kleefstra syndrome (KLEFS1) — a neurodevelopmental disorder caused by rare variants in EHMT1, which encodes an epigenetic regulator involved in H3K9 methylation.

The authors report that 70% of individuals with Kleefstra syndrome in their cohort experience severe sleep maintenance insomnia characterised by fragmented sleep and frequent night awakenings. Using model organisms, they identify a mechanism in which EHMT1/G9a function in insulin-producing cells is required for normal reactive oxygen species (ROS) homeostasis; disruption of this pathway impairs sleep maintenance across species.

This work is notable for connecting a known neurodevelopmental genetic disorder to a specific and under-characterised clinical feature — sleep disruption — via a mechanistic pathway that may be amenable to therapeutic targeting. The authors also report that common genetic variation at the EHMT1 locus is associated with short sleep and insomnia traits in the broader population, suggesting the findings may have wider implications for sleep genetics.

This work should be read alongside the recent Genetic Current cluster (1 September 2026) describing metabolic collapse in Kleefstra syndrome; that paper examined EHMT1 from the angle of developmental regression and glucose metabolism, while the present preprint focuses specifically on sleep. As a preprint, these findings have not yet been peer-reviewed, and replication in larger cohorts will be important. Researchers in rare disease genetics, neurodevelopmental disorders, and sleep genetics may find this a useful addition to the EHMT1 literature.