De novo variants in the KDM2A gene cause a syndromic neurodevelopmental disorder. Researchers identified disease-causing missense variants and variants predicted to result in loss of function in KDM2A in 18 patients exhibiting developmental delay and/or intellectual disability of varying severity. Additional core features of the condition include primary microcephaly, congenital short stature, and feeding difficulties. The affected individuals also displayed recurrent, characteristic facial features.

KDM2A belongs to the family of histone lysine demethylases (KDMs) and functions as an “eraser” within the epigenetic machinery: It specifically removes methylation marks from histones (H3K36me1/2), thereby playing a crucial role in gene regulation and key cellular processes such as cell division, differentiation, and programmed cell death.

The authors of the study, which was recently published in the American Journal of Human Genetics, investigated the disease-causing effects of identified KDM2A variants in experiments in human cells and a Drosophila model. Knockdown/Knockout of the fly’s orthologous Kdm2 gene (the counterpart to human KDM2A/KDM2B) alone did not produce noticeable degenerative or motor phenotypes. However, introducing the pathogenic human KDM2A variant in addition led to neurodegeneration, motor deficits, and shortened lifespan. The researchers therefore assume a dual mechanism in which loss of KDM2A nuclear function is accompanied by cytoplasmic toxicity resulting from a gain of function of the p.Pro235Leu variant. Moreover, methylation profiling revealed a distinctive, KDM2A-specific episignature in the majority of their patients.