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)

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 CHU Pontchaillou [Rennes]
9 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
10 GPMCND - Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques
11 UNIROUEN UFR Santé - UNIROUEN - UFR Santé
12 HCL - Hospices Civils de Lyon
13 CRNL - Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center
14 CHLS - Centre Hospitalier Lyon Sud [CHU - HCL]
15 Equipe GAD (LNC - U1231)
16 Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)
17 iBrain - Inserm U1253 - UNIV Tours - Imagerie et cerveau
18 VU University Medical Center [Amsterdam]
19 EDC (UMR_7216) - Centre épigénétique et destin cellulaire
20 EDC (UMR_7216) - Centre épigénétique et destin cellulaire
21 IRCCS - Istituto di Ricovero e Cura a Carattere Scientifico
22 Cellular Immunology Unit, Division of Immunology, Transplantation and Infectious Diseases [IRCSS San Raffaele Scientific Institute, Milan]
23 AP-HP - Assistance publique - Hôpitaux de Paris (AP-HP)
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 [Hobart, Australia]
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)

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: Molecular diagnostics; EpiSign; VUS classification; Episignature; DNA methylation; Uncertain clinical cases

Domains: Life Sciences [q-bio]

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, 2020, 106 (3), pp.356-370. ⟨10.1016/j.ajhg.2020.01.019⟩. ⟨hal-02538107⟩