University of Manchester identifies seven new EHMT2 gene variants

Researchers at the University of Manchester have identified seven new de-novo variants in the EHMT2 gene that display clear molecular and clinical parallels to Kleefstra syndrome 1, according to findings published in Nature Communications. The study examines how these genetic changes disrupt epigenetic balance and provides new insight into rare developmental disorders.

Molecular Mechanisms of EHMT2 Variants

The EHMT2 gene encodes the G9a enzyme, which controls gene activity through specific histone methylations. Analysis by the research team showed that the newly identified variants lead to stable but catalytically inactive G9a proteins. Despite losing their enzymatic function, these proteins remain intact within the cellular environment. This indicates that the disease mechanism stems from complex interactions inside the epigenetic network rather than a simple absence of the protein.

Validation Through Heterozygous Mouse Models

To test these molecular effects in a living organism, the scientists studied heterozygous mouse models carrying a patient-derived variant. These animals exhibited significant growth retardation along with characteristic changes in skull and facial structure. Researchers also observed distinct behavioral abnormalities in the test models. These traits match core symptoms observed in patients during clinical routines, confirming the functional relevance of the genetic deviations.

Classification as an Autosomal-Dominant Condition

The collected data suggest that the identified EHMT2 variants act through a dominant-negative mechanism. In this process, the altered, non-functional protein disrupts remaining intact units in the cellular network, driving profound developmental disorders. Based on these findings, the research team proposes classifying the phenomenon as a distinct, autosomal-dominant EHMT2-associated Kleefstra syndrome under Digital Object Identifier 10.1038/s41467-026-74987-w.