De novo variants in KDM2A cause a syndromic neurodevelopmental disorder.

Germline variants that disrupt components of the epigenetic machinery cause syndromic neurodevelopmental disorders. Using exome and genome sequencing, we identified de novo variants in KDM2A, a lysine demethylase crucial for embryonic development, in 18 individuals with developmental delays and/or intellectual disabilities. The severity ranged from learning disabilities to severe intellectual disability. Other core symptoms included feeding difficulties, growth issues such as intrauterine growth restriction, short stature and microcephaly as well as recurrent facial features like epicanthic folds, upslanted palpebral fissures, thin lips, and low-set ears. Expression of human disease-causing KDM2A variants in a Drosophila melanogaster model led to neural degeneration, motor defects, and reduced lifespan. Interestingly, pathogenic variants in KDM2A affected physiological attributes including subcellular distribution, expression and stability in human cells. Genetic epistasis experiments indicated that KDM2A variants likely exert their effects through a potential gain-of-function mechanism, as eliminating endogenous KDM2A in Drosophila did not produce noticeable neurodevelopmental phenotypes. Data from Enzymatic-Methylation sequencing supports the suggested gene-disease association by showing an aberrant methylome profiles in affected individuals' peripheral blood. Combining our genetic, phenotypic and functional findings, we establish de novo variants in KDM2A as causative for a syndromic neurodevelopmental disorder.