Clinical epigenomics: genome-wide DNA methylation analysis for the diagnosis of Mendelian disorders

Bekim Sadikovic*, Michael A. Levi, Jennifer Kerkhof, Erfan Aref-Eshghi, Laila Schenkel, Alan Stuart, Haley McConkey, Peter Henneman, Andrea Venema, Charles E. Schwartz, Roger E. Stevenson, Steven A. Skinner, Barbara R. DuPont, Robin S. Fletcher, Tugce B. Balci, Victoria Mok Siu, Jorge L. Granadillo, Jennefer Masters, Mike Kadour, Michael J. FriezMieke M. van Haelst, Marcel M.A.M. Mannens, Raymond J. Louie, Jennifer A. Lee, Matthew L. Tedder, Marielle Alders

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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.

Original languageEnglish
Pages (from-to)1065-1074
Number of pages10
JournalGenetics in Medicine
Issue number6
Publication statusPublished - Jun 2021

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