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

Canada DNA Methylation Epigenomics Europe Humans Syndrome

Journal

Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831

Informations de publication

Date de publication:
06 2021
Historique:
received: 27 08 2020
accepted: 31 12 2020
revised: 29 12 2020
pubmed: 7 2 2021
medline: 8 7 2021
entrez: 6 2 2021
Statut: ppublish

Résumé

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. 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). 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. 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.

Identifiants

DOI: 10.1038/s41436-020-01096-4 PMID: 33547396 PMC: PMC8187150
pubmed: 33547396
doi: 10.1038/s41436-020-01096-4
pii: S1098-3600(21)05210-2
pmc: PMC8187150
doi:

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

1065-1074

Commentaires et corrections

Type : ErratumIn

Références

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Auteurs

Bekim Sadikovic (B)

Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON, Canada. Bekim.Sadikovic@lhsc.on.ca.
Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada. Bekim.Sadikovic@lhsc.on.ca.
ORCID: 0000-0001-6363-0016

Michael A Levy (MA)

Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON, Canada.
Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada.

Jennifer Kerkhof (J)

Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON, Canada.
Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada.

Erfan Aref-Eshghi (E)

Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON, Canada.
Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada.

Laila Schenkel (L)

Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON, Canada.
Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada.

Alan Stuart (A)

Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON, Canada.
Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada.

Haley McConkey (H)

Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON, Canada.
Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada.

Peter Henneman (P)

Amsterdam University Medical Center, University of Amsterdam, Department of Clinical Genetics, Amsterdam Reproduction and Development Research Institute, Amsterdam, The Netherlands.

Andrea Venema (A)

Amsterdam University Medical Center, University of Amsterdam, Department of Clinical Genetics, Amsterdam Reproduction and Development Research Institute, Amsterdam, The Netherlands.

Charles E Schwartz (CE)

Greenwood Genetic Center, Greenwood, SC, USA.

Roger E Stevenson (RE)

Greenwood Genetic Center, Greenwood, SC, USA.

Steven A Skinner (SA)

Greenwood Genetic Center, Greenwood, SC, USA.

Barbara R DuPont (BR)

Greenwood Genetic Center, Greenwood, SC, USA.

Robin S Fletcher (RS)

Greenwood Genetic Center, Greenwood, SC, USA.

Tugce B Balci (TB)

Department of Pediatrics, Division of Medical Genetics, Western University, London, ON, Canada.
Medical Genetics Program of Southwestern Ontario, London Health Sciences Centre, London, ON, Canada.

Victoria Mok Siu (VM)

Department of Pediatrics, Division of Medical Genetics, Western University, London, ON, Canada.
Medical Genetics Program of Southwestern Ontario, London Health Sciences Centre, London, ON, Canada.

Jorge L Granadillo (JL)

Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.

Jennefer Masters (J)

Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON, Canada.
Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada.

Mike Kadour (M)

Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON, Canada.
Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada.

Michael J Friez (MJ)

Greenwood Genetic Center, Greenwood, SC, USA.

Mieke M van Haelst (MM)

Amsterdam University Medical Center, University of Amsterdam, Department of Clinical Genetics, Amsterdam Reproduction and Development Research Institute, Amsterdam, The Netherlands.

Marcel M A M Mannens (MMAM)

Amsterdam University Medical Center, University of Amsterdam, Department of Clinical Genetics, Amsterdam Reproduction and Development Research Institute, Amsterdam, The Netherlands.

Raymond J Louie (RJ)

Greenwood Genetic Center, Greenwood, SC, USA.

Jennifer A Lee (JA)

Greenwood Genetic Center, Greenwood, SC, USA.

Matthew L Tedder (ML)

Greenwood Genetic Center, Greenwood, SC, USA. mtedder@ggc.org.

Marielle Alders (M)

Amsterdam University Medical Center, University of Amsterdam, Department of Clinical Genetics, Amsterdam Reproduction and Development Research Institute, Amsterdam, The Netherlands. m.alders@amsterdamumc.nl.

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