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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 Valérie Cormier-Daire 8 Sophie Rondeau 8 François Lecoquierre 9 Pascale Saugier-Veber 9 Gaël Nicolas 10, 9 Gaetan Lesca 11 Nicolas Chatron 12 Damien Sanlaville 13 Antonio Vitobello 14 Laurence Faivre 15 Christel Thauvin-Robinet 15 Frédéric Laumonnier 16 Martine Raynaud 16 Marielle Alders 17 Marcel Mannens 17 Peter Henneman 17 Raoul Hennekam 17 Guillaume Velasco 18 Claire Francastel 18 Damien Ulveling 19 Andrea Ciolfi 20 Simone Pizzi 21 Marco Tartaglia 20 Solveig Heide 22 Delphine Heron 22 Cyril Mignot 22 Boris Keren 23 Sandra Whalen 24 Alexandra Afenjar 22 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
1 LHSC - London Health Sciences Center
2 Schulich School of Medicine and Dentistry
3 CHU Montpellier
4 IGMM - Institut de Génétique Moléculaire de Montpellier
5 Service de génétique médicale
6 UB - Université de Bordeaux
7 U1211 INSERM/MRGM - Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux)
8 IMAGINE - U1163 - Imagine - Institut des maladies génétiques
9 GPMCND - Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques
10 UNIROUEN UFR Santé - UNIROUEN - UFR Santé
11 HCL - Hospices Civils de Lyon
12 CRNL - Centre de recherche en neurosciences de Lyon
13 CHLS - Centre Hospitalier Lyon Sud [CHU - HCL]
14 Equipe GAD (LNC - U1231)
LNC - Lipides - Nutrition - Cancer [Dijon - U1231]
15 Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)
16 Imagerie et cerveau
17 VU University Medical Center [Amsterdam]
18 EDC (UMR_7216) - Centre épigénétique et destin cellulaire
19 EDC (UMR_7216) - Centre épigénétique et destin cellulaire
20 IRCCS - Istituto di Ricovero e Cura a Carattere Scientifico
21 Cellular Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases [IRCSS San Raffaele Scientific Institute, Milan]
22 AP-HP - Assistance publique - Hôpitaux de Paris (AP-HP)
23 Service de Génétique et Cytogénétique [CHU Pitié-Salpêtrière]
24 Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière]
25 Service de biochimie et de génétique moléculaire [CHU Cochin]
26 CHU Sainte Justine [Montréal]
27 McMaster University [Hamilton, Ontario]
28 UWO - University of Western Ontario
29 UTAS - University of Tasmania
30 Shinshu University Hospital
31 Radboud University Medical Center [Nijmegen]
32 Hunter Genetics
33 UND - University of Notre Dame [Indiana]
34 University of South Australia [Adelaide]
35 The Greenwood Genetic Center
36 Greenwood Genetic Center [Greenwood, South Carolina, USA]
37 Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB)
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.
Keywords : Uncertain clinical cases VUS classification Molecular diagnostics EpiSign Episignature DNA methylation
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Journal articles
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https://hal-normandie-univ.archives-ouvertes.fr/hal-02538107
Contributor : Nathalie Porchet <>
Submitted on : Thursday, April 9, 2020 - 11:25:00 AM
Last modification on : Wednesday, October 14, 2020 - 3:54:57 AM

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COMUE-NORMANDIE | UNIV-BOURGOGNE | HCL | UNIV-ST-ETIENNE | LNC-UMR866 | UNIV-LYON1 | BIOSIT | LNC-GAD | UR1-UFR-SVE | UNIV-MONTPELLIER | UNIROUEN | SORBONNE-UNIVERSITE | UNIV-TOURS | GPMCND | CNRS | UDL | BS | UNIV-PARIS | UP-SCIENCES | IRSET | CHLS | UP-SANTE

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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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