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. Friez; Mieke M. van Haelst; Marcel M.A.M. Mannens; Raymond J. Louie; Jennifer A. Lee; Matthew L. Tedder; Marielle Alders

doi:https://doi.org/10.1038/s41436-020-01096-4

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

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

83 Citations (Scopus)

Abstract

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 language	English
Pages (from-to)	1065-1074
Number of pages	10
Journal	Genetics in medicine
Volume	23
Issue number	6
Early online date	2021
DOIs	https://doi.org/10.1038/s41436-020-01096-4
Publication status	Published - Jun 2021

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Sadikovic, B., Levi, M. A., Kerkhof, J., Aref-Eshghi, E., Schenkel, L., Stuart, A., McConkey, H., Henneman, P., Venema, A., Schwartz, C. E., Stevenson, R. E., Skinner, S. A., DuPont, B. R., Fletcher, R. S., Balci, T. B., Siu, V. M., Granadillo, J. L., Masters, J., Kadour, M., ... Alders, M. (2021). Clinical epigenomics: genome-wide DNA methylation analysis for the diagnosis of Mendelian disorders. Genetics in medicine, 23(6), 1065-1074. https://doi.org/10.1038/s41436-020-01096-4

@article{b0f0b98ce3d84f8f90ab346fb97a3ced,

title = "Clinical epigenomics: genome-wide DNA methylation analysis for the diagnosis of Mendelian disorders",

abstract = "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.",

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

year = "2021",

month = jun,

doi = "https://doi.org/10.1038/s41436-020-01096-4",

language = "English",

volume = "23",

pages = "1065--1074",

journal = "Genetics in medicine",

issn = "1098-3600",

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number = "6",

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Sadikovic, B, Levi, MA, Kerkhof, J, Aref-Eshghi, E, Schenkel, L, Stuart, A, McConkey, H, Henneman, P , Venema, A, Schwartz, CE, Stevenson, RE, Skinner, SA, DuPont, BR, Fletcher, RS, Balci, TB, Siu, VM, Granadillo, JL, Masters, J, Kadour, M, Friez, MJ, van Haelst, MM , Mannens, MMAM, Louie, RJ, Lee, JA, Tedder, ML & Alders, M 2021, 'Clinical epigenomics: genome-wide DNA methylation analysis for the diagnosis of Mendelian disorders', Genetics in medicine, vol. 23, no. 6, pp. 1065-1074. https://doi.org/10.1038/s41436-020-01096-4

TY - JOUR

T1 - Clinical epigenomics

T2 - genome-wide DNA methylation analysis for the diagnosis of Mendelian disorders

AU - Sadikovic, Bekim

AU - Levi, 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

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.

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U2 - https://doi.org/10.1038/s41436-020-01096-4

DO - https://doi.org/10.1038/s41436-020-01096-4

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SN - 1098-3600

VL - 23

SP - 1065

EP - 1074

JO - Genetics in medicine

JF - Genetics in medicine

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ER -

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

Abstract

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