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Evaluation of DNA Methylation Episignatures for Diagnosis and Phenotype Correlations in 42 Mendelian Neurodevelopmental Disorders

Erfan Aref-Eshghi 1 Jennifer Kerkhof 1 Victor Pedro 2 Mouna Barat-Houari 3 Nathalie Ruiz-Pallares 3 Jean-Christophe Andrau 4 Didier Lacombe 5 Julien Van-Gils 6 Patricia Fergelot 7 Christèle Dubourg 8 Valérie Cormier-Daire 9 Sophie Rondeau 9 François Lecoquierre 10 Pascale Saugier-Veber 10 Gaël Nicolas 11, 10 Gaetan Lesca 12 Nicolas Chatron 13 Damien Sanlaville 14 Antonio Vitobello 15 Laurence Faivre 16 Christel Thauvin-Robinet 16 Frédéric Laumonnier 17 Martine Raynaud 17 Marielle Alders 18 Marcel Mannens 18 Peter Henneman 18 Raoul Hennekam 18 Guillaume Velasco 19 Claire Francastel 19 Damien Ulveling 20 Andrea Ciolfi 21 Simone Pizzi 22 Marco Tartaglia 21 Solveig Heide 23 Delphine Heron 23 Cyril Mignot 23 Boris Keren 24 Sandra Whalen 24 Alexandra Afenjar 23 Thierry Bienvenu 25 Philippe Campeau 26 Justine Rousseau 26 Michael Levy 1 Lauren Brick 27 Mariya Kozenko 27 Tugce Balci 27 Victoria Mok Siu 28 Alan Stuart 1 Mike Kadour 1 Jennifer Masters 29 Kyoko Takano 30 Tjitske Kleefstra 31 Nicole de Leeuw 31 Michael Field 32 Marie Shaw 33 Jozef Gecz 34 Peter Ainsworth 1 Hanxin Lin 1 David Rodenhiser 28 Michael Friez 35 Matt Tedder 35 Jennifer Lee 35 Barbara R. Dupont 35 Roger Stevenson 35 Steven Skinner 35 Charles Schwartz 36 David Geneviève 37 Bekim Sadikovic 1, 28, * 
* Corresponding author
15 Equipe GAD (LNC - U1231)
LNC - Lipides - Nutrition - Cancer [Dijon - U1231]
Abstract : 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.
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Submitted on : Thursday, April 9, 2020 - 11:25:00 AM
Last modification on : Sunday, June 26, 2022 - 1:55:47 AM

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Erfan Aref-Eshghi, Jennifer Kerkhof, Victor Pedro, Mouna Barat-Houari, Nathalie Ruiz-Pallares, et al.. Evaluation of DNA Methylation Episignatures for Diagnosis and Phenotype Correlations in 42 Mendelian Neurodevelopmental Disorders. American Journal of Human Genetics, Elsevier (Cell Press), 2020, 106 (3), pp.356-370. ⟨10.1016/j.ajhg.2020.01.019⟩. ⟨hal-02538107⟩

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