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Clinical epigenomics: genome-wide DNA methylation analysis for the diagnosis of Mendelian disorders
Genetics in Medicine
  • Bekim Sadikovic, London Health Sciences Centre
  • Michael A. Levy, London Health Sciences Centre
  • Jennifer Kerkhof, London Health Sciences Centre
  • Erfan Aref-Eshghi, London Health Sciences Centre
  • Laila Schenkel, London Health Sciences Centre
  • Alan Stuart, London Health Sciences Centre
  • Haley McConkey, London Health Sciences Centre
  • Peter Henneman, Amsterdam UMC - University of Amsterdam
  • Andrea Venema, Amsterdam UMC - University of Amsterdam
  • Charles E. Schwartz, Greenwood Genetics Center
  • Roger E. Stevenson, Greenwood Genetics Center
  • Steven A. Skinner, Greenwood Genetics Center
  • Barbara R. DuPont, Greenwood Genetics Center
  • Robin S. Fletcher, Greenwood Genetics Center
  • Tugce B. Balci, Western University
  • Victoria Mok Siu, Western University
  • Jorge L. Granadillo, Washington University School of Medicine in St. Louis
  • Jennefer Masters, London Health Sciences Centre
  • Mike Kadour, London Health Sciences Centre
  • Michael J. Friez, Greenwood Genetics Center
  • Mieke M. van Haelst, Amsterdam UMC - University of Amsterdam
  • Marcel M.A.M. Mannens, Amsterdam UMC - University of Amsterdam
  • Raymond J. Louie, Greenwood Genetics Center
  • Jennifer A. Lee, Greenwood Genetics Center
  • Matthew L. Tedder, Greenwood Genetics Center
  • Marielle Alders, Amsterdam UMC - University of Amsterdam
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Purpose: We describe the clinical implementation of genome-wide DNA methylation analysis in rare disorders across the EpiSign diagnostic laboratory network and the assessment of results and clinical impact in the first subjects tested. Methods: We outline the logistics and data flow between an integrated network of clinical diagnostics laboratories in Europe, the United States, and Canada. We describe the clinical validation of EpiSign using 211 specimens and assess the test performance and diagnostic yield in the first 207 subjects tested involving two patient subgroups: the targeted cohort (subjects with previous ambiguous/inconclusive genetic findings including genetic variants of unknown clinical significance) and the screening cohort (subjects with clinical findings consistent with hereditary neurodevelopmental syndromes and no previous conclusive genetic findings). Results: Among the 207 subjects tested, 57 (27.6%) were positive for a diagnostic episignature including 48/136 (35.3%) in the targeted cohort and 8/71 (11.3%) in the screening cohort, with 4/207 (1.9%) remaining inconclusive after EpiSign analysis. Conclusion: This study describes the implementation of diagnostic clinical genomic DNA methylation testing in patients with rare disorders. It provides strong evidence of clinical utility of EpiSign analysis, including the ability to provide conclusive findings in the majority of subjects tested.

Citation Information
Bekim Sadikovic, Michael A. Levy, Jennifer Kerkhof, Erfan Aref-Eshghi, et al.. "Clinical epigenomics: genome-wide DNA methylation analysis for the diagnosis of Mendelian disorders" Genetics in Medicine Vol. 23 Iss. 6 (2021) p. 1065 - 1074
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