TY - JOUR
T1 - Clinical epigenomics
T2 - genome-wide DNA methylation analysis for the diagnosis of Mendelian disorders
AU - Sadikovic, Bekim
AU - Levy, Michael A.
AU - Kerkhof, Jennifer
AU - Aref-Eshghi, Erfan
AU - Schenkel, Laila
AU - Stuart, Alan
AU - McConkey, Haley
AU - Henneman, Peter
AU - Venema, Andrea
AU - Schwartz, Charles E.
AU - Stevenson, Roger E.
AU - Skinner, Steven A.
AU - DuPont, Barbara R.
AU - Fletcher, Robin S.
AU - Balci, Tugce B.
AU - Siu, Victoria Mok
AU - Granadillo, Jorge L.
AU - Masters, Jennefer
AU - Kadour, Mike
AU - Friez, Michael J.
AU - van Haelst, Mieke M.
AU - Mannens, Marcel M.A.M.
AU - Louie, Raymond J.
AU - Lee, Jennifer A.
AU - Tedder, Matthew L.
AU - Alders, Marielle
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2021/6
Y1 - 2021/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85100548502&partnerID=8YFLogxK
U2 - 10.1038/s41436-020-01096-4
DO - 10.1038/s41436-020-01096-4
M3 - Article
C2 - 33547396
AN - SCOPUS:85100548502
SN - 1098-3600
VL - 23
SP - 1065
EP - 1074
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 6
ER -