The discovery of the DNA methylation episignature for Duchenne muscular dystrophy

Leighton Schreyer; Jack Reilly; Haley McConkey; Jennifer Kerkhof; Michael A Levy; Jonathan Hu; Mona Hnaini; Bekim Sadikovic; Craig Campbell

doi:10.1016/j.nmd.2022.12.003

The discovery of the DNA methylation episignature for Duchenne muscular dystrophy

Neuromuscul Disord. 2023 Jan;33(1):5-14. doi: 10.1016/j.nmd.2022.12.003. Epub 2022 Dec 7.

Authors

Leighton Schreyer¹, Jack Reilly², Haley McConkey³, Jennifer Kerkhof³, Michael A Levy³, Jonathan Hu⁴, Mona Hnaini⁵, Bekim Sadikovic⁶, Craig Campbell⁷

Affiliations

¹ Department of Neuroscience, Western University, London, ON N6A 3K7, Canada.
² Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada; Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON N6A 5W9, Canada.
³ Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON N6A 5W9, Canada.
⁴ Department of Medicine, Schulich School of Medicine & Dentistry, Western University, London, ON N6A 3K7, Canada.
⁵ Department of Pediatrics, Clinical Neurological Sciences, Western University, London, ON N6A 3K7, Canada.
⁶ Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada; Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON N6A 5W9, Canada. Electronic address: bekim.sadikovic@lhsc.on.ca.
⁷ Department of Pediatrics, Clinical Neurological Sciences and Epidemiology, Western University, London, ON N6A 3K7, Canada. Electronic address: craig.campbell@lhsc.on.ca.

PMID: 36572586
DOI: 10.1016/j.nmd.2022.12.003

Abstract

Duchenne Muscular Dystrophy (DMD) is an X-linked recessive neuromuscular disorder characterized by progressive muscle weakness due to loss of function mutations in the dystrophin gene. Variation in clinical presentation, the rate of disease progression, and treatment responsiveness have been observed amongst DMD patients, suggesting that factors beyond the loss of dystrophin may contribute to DMD pathophysiology. Epigenetic mechanisms are becoming recognized as important factors implicated in the etiology and progression of various diseases. A growing number of genetic syndromes have been associated with unique genomic DNA methylation patterns (called "episignatures") that can be used for diagnostic testing and as disease biomarkers. To further investigate DMD pathophysiology, we assessed the genome-wide DNA methylation profiles of peripheral blood from 36 patients with DMD using the combination of Illumina Infinium Methylation EPIC bead chip array and EpiSign technology. We identified a unique episignature for DMD that whose specificity was confirmed in relation other neurodevelopmental disorders with known episignatures. By modeling the DMD episignature, we developed a new DMD episignature biomarker and provided novel insights into the molecular pathogenesis of this disorder, which have the potential to advance more effective, personalized approaches to DMD care.

Keywords: DNA methylation; Disease screening; Duchenne muscular dystrophy; Epigenetics; Episignature.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

DNA Methylation
Dystrophin / genetics
Dystrophin / metabolism
Humans
Muscular Dystrophy, Duchenne* / diagnosis
Muscular Dystrophy, Duchenne* / genetics
Muscular Dystrophy, Duchenne* / pathology

Substances

Dystrophin