Functional Insight into and Refinement of the Genomic Boundaries of the -Neurodevelopmental Disorder Episignature.

(Jumonji, AT-rich interactive domain 2) haploinsufficiency is associated with a clinically distinct neurodevelopmental syndrome. It is characterized by intellectual disability, developmental delay, autistic features, behavior abnormalities, cognitive impairment, hypotonia, and dysmorphic features. acts as a transcriptional repressor protein that is involved in the regulation of histone methyltransferase complexes. plays a role in the epigenetic machinery, and the associated syndrome has an identified DNA methylation episignature derived from sequence variants and intragenic deletions involving . For this study, our aim was to determine whether patients with larger deletions spanning beyond present a similar DNA methylation episignature and to define the critical region involved in aberrant DNA methylation in 6p22-p24 microdeletions. We examined the DNA methylation profiles of peripheral blood from 56 control subjects, 13 patients with (likely) pathogenic variants or patients carrying copy number variants, and three patients with VUS variants. The analysis showed a distinct and strong differentiation between patients with (likely) pathogenic variants, both sequence and copy number, and controls. Using the identified episignature, we developed a binary model to classify patients with the -neurodevelopmental syndrome. DNA methylation analysis indicated that is the driver gene for aberrant DNA methylation observed in 6p22-p24 microdeletions. In addition, we performed analysis of functional correlation of the genome-wide methylation profile with the DNA methylation profiles of 56 additional neurodevelopmental disorders. To conclude, we refined the critical region for the presence of the episignature in 6p22-p24 microdeletions and provide insight into the functional changes in the epigenome observed when regulation by is lost.