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Clinical epigenomics: genome-wide DNA methylation analysis for the diagnosis of Mendelian disorders.
Sadikovic, Bekim; Levy, Michael A; Kerkhof, Jennifer; Aref-Eshghi, Erfan; Schenkel, Laila; Stuart, Alan; McConkey, Haley; Henneman, Peter; Venema, Andrea; Schwartz, Charles E; Stevenson, Roger E; Skinner, Steven A; DuPont, Barbara R; Fletcher, Robin S; Balci, Tugce B; Siu, Victoria Mok; Granadillo, Jorge L; Masters, Jennefer; Kadour, Mike; Friez, Michael J; van Haelst, Mieke M; Mannens, Marcel M A M; Louie, Raymond J; Lee, Jennifer A; Tedder, Matthew L; Alders, Marielle.
Afiliação
  • Sadikovic B; Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON, Canada. Bekim.Sadikovic@lhsc.on.ca.
  • Levy MA; Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada. Bekim.Sadikovic@lhsc.on.ca.
  • Kerkhof J; Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON, Canada.
  • Aref-Eshghi E; Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada.
  • Schenkel L; Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON, Canada.
  • Stuart A; Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada.
  • McConkey H; Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON, Canada.
  • Henneman P; Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada.
  • Venema A; Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON, Canada.
  • Schwartz CE; Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada.
  • Stevenson RE; Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON, Canada.
  • Skinner SA; Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada.
  • DuPont BR; Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON, Canada.
  • Fletcher RS; Department of Pathology and Laboratory Medicine, Western University, London, ON, Canada.
  • Balci TB; Amsterdam University Medical Center, University of Amsterdam, Department of Clinical Genetics, Amsterdam Reproduction and Development Research Institute, Amsterdam, The Netherlands.
  • Siu VM; Amsterdam University Medical Center, University of Amsterdam, Department of Clinical Genetics, Amsterdam Reproduction and Development Research Institute, Amsterdam, The Netherlands.
  • Granadillo JL; Greenwood Genetic Center, Greenwood, SC, USA.
  • Masters J; Greenwood Genetic Center, Greenwood, SC, USA.
  • Kadour M; Greenwood Genetic Center, Greenwood, SC, USA.
  • Friez MJ; Greenwood Genetic Center, Greenwood, SC, USA.
  • van Haelst MM; Greenwood Genetic Center, Greenwood, SC, USA.
  • Mannens MMAM; Department of Pediatrics, Division of Medical Genetics, Western University, London, ON, Canada.
  • Louie RJ; Medical Genetics Program of Southwestern Ontario, London Health Sciences Centre, London, ON, Canada.
  • Lee JA; Department of Pediatrics, Division of Medical Genetics, Western University, London, ON, Canada.
  • Tedder ML; Medical Genetics Program of Southwestern Ontario, London Health Sciences Centre, London, ON, Canada.
  • Alders M; Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.
Genet Med ; 23(6): 1065-1074, 2021 06.
Article em En | MEDLINE | ID: mdl-33547396
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Metilação de DNA / Epigenômica Tipo de estudo: Diagnostic_studies Limite: Humans País como assunto: America do norte / Europa Idioma: En Ano de publicação: 2021 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Metilação de DNA / Epigenômica Tipo de estudo: Diagnostic_studies Limite: Humans País como assunto: America do norte / Europa Idioma: En Ano de publicação: 2021 Tipo de documento: Article