TY - JOUR
T1 - Evaluation of DNA Methylation Episignatures for Diagnosis and Phenotype Correlations in 42 Mendelian Neurodevelopmental Disorders
AU - Groupe DI France
AU - Aref-Eshghi, Erfan
AU - Kerkhof, Jennifer
AU - Pedro, Victor P.
AU - Barat-Houari, Mouna
AU - Ruiz-Pallares, Nathalie
AU - Andrau, Jean-Christophe
AU - Lacombe, Didier
AU - van-Gils, Julien
AU - Fergelot, Patricia
AU - Dubourg, Christèle
AU - Cormier-Daire, Valerie
AU - Rondeau, Sophie
AU - Lecoquierre, François
AU - Saugier-Veber, Pascale
AU - Nicolas, Gaël
AU - Lesca, Gaetan
AU - Chatron, Nicolas
AU - Sanlaville, Damien
AU - Vitobello, Antonio
AU - Faivre, Laurence
AU - Thauvin-Robinet, Christel
AU - Laumonnier, Frederic
AU - Raynaud, Martine
AU - Alders, Mariëlle
AU - Mannens, Marcel
AU - Henneman, Peter
AU - Hennekam, Raoul C.
AU - Velasco, Guillaume
AU - Francastel, Claire
AU - Ulveling, Damien
AU - Ciolfi, Andrea
AU - Pizzi, Simone
AU - Tartaglia, Marco
AU - Heide, Solveig
AU - Héron, Delphine
AU - Mignot, Cyril
AU - Keren, Boris
AU - Whalen, Sandra
AU - Afenjar, Alexandra
AU - Bienvenu, Thierry
AU - Campeau, Philippe M.
AU - Rousseau, Justine
AU - Levy, Michael A.
AU - Brick, Lauren
AU - Kozenko, Mariya
AU - Balci, Tugce B.
AU - Siu, Victoria Mok
AU - Stuart, Alan
AU - Kadour, Mike
AU - Masters, Jennifer
PY - 2020/3/5
Y1 - 2020/3/5
N2 - 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.
AB - 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.
KW - DNA methylation
KW - EpiSign
KW - VUS classification
KW - episignature
KW - molecular diagnostics
KW - uncertain clinical cases
UR - http://www.scopus.com/inward/record.url?scp=85080133265&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.ajhg.2020.01.019
DO - https://doi.org/10.1016/j.ajhg.2020.01.019
M3 - Article
C2 - 32109418
SN - 0002-9297
VL - 106
SP - 356
EP - 370
JO - American journal of human genetics
JF - American journal of human genetics
IS - 3
ER -