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Evaluation of DNA Methylation Episignatures for Diagnosis and Phenotype Correlations in 42 Mendelian Neurodevelopmental Disorders.
American Journal of Human Genetics
  • Erfan Aref-Eshghi
  • Jennifer Kerkhof
  • Victor P Pedro
  • Mouna Barat-Houari
  • Nathalie Ruiz-Pallares
  • Jean-Christophe Andrau
  • Didier Lacombe
  • Julien Van-Gils
  • Patricia Fergelot
  • Christèle Dubourg
  • Valerie Cormier-Daire
  • Sophie Rondeau
  • François Lecoquierre
  • Pascale Saugier-Veber
  • Gaël Nicolas
  • Gaetan Lesca
  • Nicolas Chatron
  • Damien Sanlaville
  • Antonio Vitobello
  • Laurence Faivre
  • Christel Thauvin-Robinet
  • Frederic Laumonnier
  • Martine Raynaud
  • Mariëlle Alders
  • Marcel Mannens
  • Peter Henneman
  • Raoul C Hennekam
  • Guillaume Velasco
  • Claire Francastel
  • Damien Ulveling
  • Andrea Ciolfi
  • Simone Pizzi
  • Marco Tartaglia
  • Solveig Heide
  • Delphine Héron
  • Cyril Mignot
  • Boris Keren
  • Sandra Whalen
  • Alexandra Afenjar
  • Thierry Bienvenu
  • Philippe M Campeau
  • Justine Rousseau
  • Michael A Levy
  • Lauren Brick
  • Mariya Kozenko
  • Tugce B Balci
  • Victoria Mok Siu
  • Alan Stuart
  • Mike Kadour
  • Jennifer Masters
  • Kyoko Takano
  • Tjitske Kleefstra
  • Nicole de Leeuw
  • Michael Field
  • Marie Shaw
  • Jozef Gecz
  • Peter J Ainsworth
  • Hanxin Lin
  • David I Rodenhiser
  • Michael J Friez
  • Matt Tedder
  • Jennifer A Lee
  • Barbara R DuPont
  • Roger E Stevenson
  • Steven A Skinner
  • Charles E Schwartz
  • David Genevieve
  • Bekim Sadikovic
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Genetic syndromes frequently present with overlapping clinical features and inconclusive or ambiguous genetic findings which can confound accurate diagnosis and clinical management. An expanding number of genetic syndromes have been shown to have unique genomic DNA methylation patterns (called "episignatures"). Peripheral blood episignatures can be used for diagnostic testing as well as for the interpretation of ambiguous genetic test results. We present here an approach to episignature mapping in 42 genetic syndromes, which has allowed the identification of 34 robust disease-specific episignatures. We examine emerging patterns of overlap, as well as similarities and hierarchical relationships across these episignatures, to highlight their key features as they are related to genetic heterogeneity, dosage effect, unaffected carrier status, and incomplete penetrance. We demonstrate the necessity of multiclass modeling for accurate genetic variant classification and show how disease classification using a single episignature at a time can sometimes lead to classification errors in closely related episignatures. We demonstrate the utility of this tool in resolving ambiguous clinical cases and identification of previously undiagnosed cases through mass screening of a large cohort of subjects with developmental delays and congenital anomalies. This study more than doubles the number of published syndromes with DNA methylation episignatures and, most significantly, opens new avenues for accurate diagnosis and clinical assessment in individuals affected by these disorders.

Citation Information
Erfan Aref-Eshghi, Jennifer Kerkhof, Victor P Pedro, Mouna Barat-Houari, et al.. "Evaluation of DNA Methylation Episignatures for Diagnosis and Phenotype Correlations in 42 Mendelian Neurodevelopmental Disorders." American Journal of Human Genetics Vol. 106 Iss. 3 (2020) p. 356 - 370
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