Methylation assay in KMT2B-related dystonia: a novel diagnostic validation tool
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...
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BMC
2024-11-01
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| Series: | Clinical Epigenetics |
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| Online Access: | https://doi.org/10.1186/s13148-024-01780-1 |
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| author | Gleyson Francisco da Silva Carvalho Claudio Melo de Gusmão Beatriz Martins Wolff Lucas Liro Vieira Yanca Gasparini de Oliveira Mariana Ribeiro Costa Rafaela da Silva Mendes Matheus Augusto Araujo Castro Mayara T. Sakuma Fernando Kok Bekim Sadikovic Leslie Domenici Kulikowski |
| author_facet | Gleyson Francisco da Silva Carvalho Claudio Melo de Gusmão Beatriz Martins Wolff Lucas Liro Vieira Yanca Gasparini de Oliveira Mariana Ribeiro Costa Rafaela da Silva Mendes Matheus Augusto Araujo Castro Mayara T. Sakuma Fernando Kok Bekim Sadikovic Leslie Domenici Kulikowski |
| author_sort | Gleyson Francisco da Silva Carvalho |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-e38394b069fe409d83aec71fa3b2331e |
| institution | OA Journals |
| issn | 1868-7083 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | BMC |
| record_format | Article |
| series | Clinical Epigenetics |
| spelling | doaj-art-e38394b069fe409d83aec71fa3b2331e2025-08-20T02:08:19ZengBMCClinical Epigenetics1868-70832024-11-011611610.1186/s13148-024-01780-1Methylation assay in KMT2B-related dystonia: a novel diagnostic validation toolGleyson Francisco da Silva Carvalho0Claudio Melo de Gusmão1Beatriz Martins Wolff2Lucas Liro Vieira3Yanca Gasparini de Oliveira4Mariana Ribeiro Costa5Rafaela da Silva Mendes6Matheus Augusto Araujo Castro7Mayara T. Sakuma8Fernando Kok9Bekim Sadikovic10Leslie Domenici Kulikowski11Laboratorio de Citogenomica, Departamento de Patologia, Faculdade de Medicina FMUSP, Universidade de Sao PauloDepartamento de Neurologia, HC-FMUSPLaboratorio de Citogenomica, Departamento de Patologia, Faculdade de Medicina FMUSP, Universidade de Sao PauloLaboratorio de Citogenomica, Departamento de Patologia, Faculdade de Medicina FMUSP, Universidade de Sao PauloLaboratorio de Citogenomica, Departamento de Patologia, Faculdade de Medicina FMUSP, Universidade de Sao PauloLaboratorio de Citogenomica, Departamento de Patologia, Faculdade de Medicina FMUSP, Universidade de Sao PauloLaboratorio de Citogenomica, Departamento de Patologia, Faculdade de Medicina FMUSP, Universidade de Sao PauloDepartamento de Neurologia, HC-FMUSPDepartamento de Neurologia, HC-FMUSPDepartamento de Neurologia, HC-FMUSPMolecular Genetics Laboratory, Division of Molecular Diagnostics, London Health Sciences CentreLaboratorio de Citogenomica, Departamento de Patologia, Faculdade de Medicina FMUSP, Universidade de Sao PauloAbstract 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.https://doi.org/10.1186/s13148-024-01780-1KMT2BMethylationEpisignatureVUSDystonia |
| spellingShingle | Gleyson Francisco da Silva Carvalho Claudio Melo de Gusmão Beatriz Martins Wolff Lucas Liro Vieira Yanca Gasparini de Oliveira Mariana Ribeiro Costa Rafaela da Silva Mendes Matheus Augusto Araujo Castro Mayara T. Sakuma Fernando Kok Bekim Sadikovic Leslie Domenici Kulikowski Methylation assay in KMT2B-related dystonia: a novel diagnostic validation tool Clinical Epigenetics KMT2B Methylation Episignature VUS Dystonia |
| title | Methylation assay in KMT2B-related dystonia: a novel diagnostic validation tool |
| title_full | Methylation assay in KMT2B-related dystonia: a novel diagnostic validation tool |
| title_fullStr | Methylation assay in KMT2B-related dystonia: a novel diagnostic validation tool |
| title_full_unstemmed | Methylation assay in KMT2B-related dystonia: a novel diagnostic validation tool |
| title_short | Methylation assay in KMT2B-related dystonia: a novel diagnostic validation tool |
| title_sort | methylation assay in kmt2b related dystonia a novel diagnostic validation tool |
| topic | KMT2B Methylation Episignature VUS Dystonia |
| url | https://doi.org/10.1186/s13148-024-01780-1 |
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