Abstract
Background/Objectives: KMT2B-related dystonia (DYT28, OMIM #617284), is a progressive neurological condition characterized by early-onset movement disorders with autosomal dominant inheritance. In this study, we describe the use of a genome methylation epi-signature methodology to functionally validate 2 variants of uncertain significance (VUS) in the KMT2B gene.
Methods: Genome-wide methylation status was assessed using the EPIC methylation assay in peripheral blood samples from two subjects with early-onset movement disorder and missense variants of uncertain significance in the KMT2B gene (p.Leu1720Phe and p.Tyr2515Cys). After QC and normalization steps, we compared the M-values for all 144 probes, previously described as an EpiSign for KMT2B-related dystonia, between the two subjects and 14 controls individuals.
Results: The individual harboring the p.Tyr2515Cys variant exhibited a hypermethylation profile compatible with pathogenic/likely pathogenic variants in KMT2B, allowing for variant reclassification, conclusive genetic counseling, and patient stratification for deep brain stimulation. In contrast, the individual harboring the p.Leu1720Phe variant had a methylation status similar to controls, practically ruling out KMT2B-related dystonia.
Conclusion: Investigation of methylation status can be a powerful tool to determine pathogenicity when facing KMT2B variants of uncertain significance. Methylation results may optimize genetic counseling and positively impact patient care.