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.

DAC, LMD and SVM are employees of and may own stock in GeneDx, LLC. The other authors declare no competing interests.

SS is funded through Albert Rowe II endowed chair in Genetics. Research reported in this manuscript was in part supported by the NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director and the National Institute of Neurological Disorders and Stroke of the NIH under Award Numbers U01HG010218 and U01HG007708. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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This study was approved by the ethics committee of the University of Leipzig (402/16-ek).

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