Comparison of methylation episignatures in KMT2B- and KMT2D-related human disorders

Sunwoo Lee; Eguzkine Ochoa; Katy Barwick; Laura Cif; Fay Rodger; France Docquier; Bélen Pérez-Dueñas; Graeme Clark; Ezequiel Martin; Siddharth Banka; Manju A. Kurian; Eamonn R. Maher

doi:10.2217/epi-2021-0521

Comparison of methylation episignatures in KMT2B- and KMT2D-related human disorders

Sunwoo Lee
, Eguzkine Ochoa
, Katy Barwick
, Laura Cif
, Fay Rodger
, France Docquier
, Bélen Pérez-Dueñas
, Graeme Clark
, Ezequiel Martin
, Siddharth Banka
, Manju A. Kurian
, Eamonn R. Maher

Research output: Contribution to journal › Article › peer-review

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Abstract

Aim & methods: To investigate peripheral blood methylation episignatures in KMT2B-related dystonia (DYT-KMT2B), the authors undertook genome-wide methylation profiling of ∼2 M CpGs using a next-generation sequencing-based assay and compared the findings with those in controls and patients with KMT2D-related Kabuki syndrome type 1 (KS1). Results: A total of 1812 significantly differentially methylated CpG positions (false discovery rate < 0.05) were detected in DYT-KMT2B samples compared with controls. Multi-dimensional scaling analysis showed that the 10 DYT-KMT2B samples clustered together and separately from 29 controls and 10 with pathogenic variants in KMT2D. The authors found that most differentially methylated CpG positions were specific to one disorder and that all (DYT-KMT2B) and most (Kabuki syndrome type 1) methylation alterations in CpG islands were gain of methylation events. Conclusion: Using sensitive methylation profiling methodology, the authors replicated recent reports of a methylation episignature for DYT-KMT2B. These findings will facilitate the development of episignature-based assays to improve diagnostic accuracy.

Original language	English
Pages (from-to)	537-547
Number of pages	11
Journal	Epigenomics
Volume	14
Issue number	9
Early online date	4 May 2022
DOIs	https://doi.org/10.2217/epi-2021-0521
Publication status	Published - 4 May 2022

Bibliographical note

Funding

This research was co-funded by the NIHR Cambridge Biomedical Research Centre and Rosetrees Trust (to E Ochoa, S Lee and ER Maher). The University of Cambridge has received salary support (ER Maher) from the NHS in the East of England through the Clinical Academic Reserve.

Keywords

Chromatin disorders
early-onset dystonia
histone lysine methyltransferases (KMTs)
Kabuki syndrom
methylation
neurodevelopmental disorder

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10.2217/epi-2021-0521Licence: CC BY 4.0

lee-et-al-2022-comparison-of-methylation-episignatures-in-kmt2b-and-kmt2d-related-human-disorders
Copyright © 2022, The Authors. This work is licensed under the Creative Commons Attribution 4.0 License. To view a copy of this license, visit https://creativecommons.org/licenses/by/4.0/
Final published version, 2.8 MBLicence: CC BY 4.0

Cite this

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title = "Comparison of methylation episignatures in KMT2B- and KMT2D-related human disorders",

abstract = "Aim \& methods: To investigate peripheral blood methylation episignatures in KMT2B-related dystonia (DYT-KMT2B), the authors undertook genome-wide methylation profiling of ∼2 M CpGs using a next-generation sequencing-based assay and compared the findings with those in controls and patients with KMT2D-related Kabuki syndrome type 1 (KS1). Results: A total of 1812 significantly differentially methylated CpG positions (false discovery rate < 0.05) were detected in DYT-KMT2B samples compared with controls. Multi-dimensional scaling analysis showed that the 10 DYT-KMT2B samples clustered together and separately from 29 controls and 10 with pathogenic variants in KMT2D. The authors found that most differentially methylated CpG positions were specific to one disorder and that all (DYT-KMT2B) and most (Kabuki syndrome type 1) methylation alterations in CpG islands were gain of methylation events. Conclusion: Using sensitive methylation profiling methodology, the authors replicated recent reports of a methylation episignature for DYT-KMT2B. These findings will facilitate the development of episignature-based assays to improve diagnostic accuracy.",

keywords = "Chromatin disorders, early-onset dystonia, histone lysine methyltransferases (KMTs), Kabuki syndrom, methylation, neurodevelopmental disorder",

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AU - Lee, Sunwoo

AU - Ochoa, Eguzkine

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AU - Cif, Laura

AU - Rodger, Fay

AU - Docquier, France

AU - Pérez-Dueñas, Bélen

AU - Clark, Graeme

AU - Martin, Ezequiel

AU - Banka, Siddharth

AU - Kurian, Manju A.

AU - Maher, Eamonn R.

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AB - Aim & methods: To investigate peripheral blood methylation episignatures in KMT2B-related dystonia (DYT-KMT2B), the authors undertook genome-wide methylation profiling of ∼2 M CpGs using a next-generation sequencing-based assay and compared the findings with those in controls and patients with KMT2D-related Kabuki syndrome type 1 (KS1). Results: A total of 1812 significantly differentially methylated CpG positions (false discovery rate < 0.05) were detected in DYT-KMT2B samples compared with controls. Multi-dimensional scaling analysis showed that the 10 DYT-KMT2B samples clustered together and separately from 29 controls and 10 with pathogenic variants in KMT2D. The authors found that most differentially methylated CpG positions were specific to one disorder and that all (DYT-KMT2B) and most (Kabuki syndrome type 1) methylation alterations in CpG islands were gain of methylation events. Conclusion: Using sensitive methylation profiling methodology, the authors replicated recent reports of a methylation episignature for DYT-KMT2B. These findings will facilitate the development of episignature-based assays to improve diagnostic accuracy.

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KW - methylation

KW - neurodevelopmental disorder

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Comparison of methylation episignatures in KMT2B- and KMT2D-related human disorders

Abstract

Bibliographical note

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Keywords

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