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. 2024 Nov 25;16(1):169.
doi: 10.1186/s13148-024-01780-1.

Methylation assay in KMT2B-related dystonia: a novel diagnostic validation tool

Gleyson Francisco da Silva Carvalho  1 , Claudio Melo de Gusmão  2 , Beatriz Martins Wolff  3 , Lucas Liro Vieira  3 , Yanca Gasparini de Oliveira  3 , Mariana Ribeiro Costa  3 , Rafaela da Silva Mendes  3 , Matheus Augusto Araujo Castro  2 , Mayara T Sakuma  2 , Fernando Kok  2 , Bekim Sadikovic  4 , Leslie Domenici Kulikowski  3
Affiliations

Methylation assay in KMT2B-related dystonia: a novel diagnostic validation tool

Gleyson Francisco da Silva Carvalho et al. Clin Epigenetics. .

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 episignature methodology to functionally validate two 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.

Keywords: KMT2B; Dystonia; Episignature; Methylation; VUS.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: The ethics committee of the University of São Paulo approved this study (HC-FMUSP—CAPPesq 4 0809520.3.0000.0068/2021). The patients or parents of the patients signed the consent form for participation in the study. Consent for publication: All authors have agreed to have this article published. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Distribution of M values between all individuals in sample cohort. Subject 2 presents an upper deviation
Fig. 2
Fig. 2
Heatmap evidencing clustering results. Subject 2 differs substantially from control individuals, while subject 1 does not present distinction
See this image and copyright information in PMC

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