Diagnostic Utility of Genome-wide DNA Methylation Analysis in Genetically Unsolved Developmental and Epileptic Encephalopathies and Refinement of a CHD2 Episignature

Christy W. LaFlamme; Cassandra Rastin; Soham Sengupta; Helen E. Pennington; Sophie J. Russ-Hall; Amy L. Schneider; Emily S. Bonkowski; Edith P. Almanza Fuerte; Miranda Galey; Joy Goffena; Sophia B. Gibson; Talia J. Allan; Denis M. Nyaga; Nico Lieffering; Malavika Hebbar; Emily V. Walker; Daniel Darnell; Scott R. Olsen; Pandurang Kolekar; Nahdir Djekidel; Wojciech Rosikiewicz; Haley McConkey; Jennifer Kerkhof; Michael A. Levy; Raissa Relator; Dorit Lev; Tally Lerman-Sagie; Kristen L. Park; Marielle Alders; Gerarda Cappuccio; Nicolas Chatron; Leigh Demain; David Genevieve; Gaetan Lesca; Tony Roscioli; Damien Sanlaville; Matthew L. Tedder; Monika Weisz Hubshman; Shamika Ketkar; Hongzheng Dai; Kim Carlyle Worley; Jill A. Rosenfeld; Hsiao-Tuan Chao; Geoffrey Neale; Gemma L. Carvill; Zhaoming Wang; Samuel F. Berkovic; Lynette G. Sadleir; Danny E. Miller; Ingrid E. Scheffer; University of Washington Center for Rare Disease Research; Bekim Sadikovic; Heather C. Mefford

doi:10.1101/2023.10.11.23296741

Prépublication

Diagnostic Utility of Genome-wide DNA Methylation Analysis in Genetically Unsolved Developmental and Epileptic Encephalopathies and Refinement of a CHD2 Episignature

Christy W. LaFlamme, Cassandra Rastin, Soham Sengupta, Helen E. Pennington, Sophie J. Russ-Hall, Amy L. Schneider, Emily S. Bonkowski, Edith P. Almanza Fuerte, Miranda Galey, Joy Goffena, …

medRxiv

Cold Spring Harbor Laboratory Press, 1.1

12/10/2023

DOI: https://doi.org/10.1101/2023.10.11.23296741

PMID: 37873138

Résumé

Genetic and Genomic Medicine

Sequence-based genetic testing currently identifies causative genetic variants in ∼50% of individuals with developmental and epileptic encephalopathies (DEEs). Aberrant changes in DNA methylation are implicated in various neurodevelopmental disorders but remain unstudied in DEEs. Rare epigenetic variations (“epivariants”) can drive disease by modulating gene expression at single loci, whereas genome-wide DNA methylation changes can result in distinct “episignature” biomarkers for monogenic disorders in a growing number of rare diseases. Here, we interrogate the diagnostic utility of genome-wide DNA methylation array analysis on peripheral blood samples from 516 individuals with genetically unsolved DEEs who had previously undergone extensive genetic testing. We identified rare differentially methylated regions (DMRs) and explanatory episignatures to discover causative and candidate genetic etiologies in 10 individuals. We then used long-read sequencing to identify DNA variants underlying rare DMRs, including one balanced translocation, three CG-rich repeat expansions, and two copy number variants. We also identify pathogenic sequence variants associated with episignatures; some had been missed by previous exome sequencing. Although most DEE genes lack known episignatures, the increase in diagnostic yield for DNA methylation analysis in DEEs is comparable to the added yield of genome sequencing. Finally, we refine an episignature for CHD2 using an 850K methylation array which was further refined at higher CpG resolution using bisulfite sequencing to investigate potential insights into CHD2 pathophysiology. Our study demonstrates the diagnostic yield of genome-wide DNA methylation analysis to identify causal and candidate genetic causes as ∼2% (10/516) for unsolved DEE cases.

Indicateurs

1 Consultations de la notice

See more details

Détails

Titre: Diagnostic Utility of Genome-wide DNA Methylation Analysis in Genetically Unsolved Developmental and Epileptic Encephalopathies and Refinement of a CHD2 Episignature
Créateurs - sans rôle: Christy W. LaFlamme - Graduate School of Biomedical Sciences, St. Jude Children’s Research Hospital
Cassandra Rastin - Verspeeten Clinical Genome Centre, London Health Science Centre
Soham Sengupta - Center for Pediatric Neurological Disease Research, St. Jude Children’s Research Hospital
Helen E. Pennington - Department of Mathematics & Statistics, Rhodes College
Sophie J. Russ-Hall - Epilepsy Research Centre, Department of Medicine, University of Melbourne
Amy L. Schneider - Epilepsy Research Centre, Department of Medicine, University of Melbourne
Emily S. Bonkowski - St. Jude Children's Research Hospital
Edith P. Almanza Fuerte - Center for Pediatric Neurological Disease Research, St. Jude Children’s Research Hospital
Miranda Galey - Division of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children’s Hospital
Joy Goffena - Division of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children’s Hospital
Sophia B. Gibson - Department of Genome Sciences, University of Washington School of Medicine
Talia J. Allan - Epilepsy Research Centre, Department of Medicine, University of Melbourne
Denis M. Nyaga - Department of Paediatrics and Child Health, University of Otago
Nico Lieffering - Department of Paediatrics and Child Health, University of Otago
Malavika Hebbar - Division of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children’s Hospital
Emily V. Walker - Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children’s Research Hospital Memphis
Daniel Darnell - Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children’s Research Hospital Memphis
Scott R. Olsen - Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children’s Research Hospital Memphis
Pandurang Kolekar - Department of Computational Biology, St. Jude Children’s Research Hospital
Nahdir Djekidel - Center for Applied Bioinformatics, St. Jude Children’s Research Hospital
Wojciech Rosikiewicz - Center for Applied Bioinformatics, St. Jude Children’s Research Hospital
Haley McConkey - Verspeeten Clinical Genome Centre, London Health Science Centre
Jennifer Kerkhof - Verspeeten Clinical Genome Centre, London Health Science Centre
Michael A. Levy - Verspeeten Clinical Genome Centre, London Health Science Centre
Raissa Relator - Verspeeten Clinical Genome Centre, London Health Science Centre
Dorit Lev - Wolfson Medical Center
Tally Lerman-Sagie - Sackler School of Medicine, Tel-Aviv University
Kristen L. Park - Departments of Pediatrics and Neurology, University of Colorado School of Medicine
Marielle Alders - University of Amsterdam
Gerarda Cappuccio - Department of Translational Medicine, Federico II University of Naples
Nicolas Chatron - Pathophysiology and Genetics of Neuron and Muscle (PNMG), UCBL, CNRS UMR5261 - INSERM U1315
Leigh Demain - Manchester Centre for Genomic Medicine
David Genevieve - Montpellier University, Reference Center for Rare Disease, Medical Genetic Department for Rare Disease and Personalize Medicine
Gaetan Lesca - Pathophysiology and Genetics of Neuron and Muscle (PNMG), UCBL, CNRS UMR5261 - INSERM U1315
Tony Roscioli - Sydney Children's Hospital
Damien Sanlaville - Pathophysiology and Genetics of Neuron and Muscle (PNMG), UCBL, CNRS UMR5261 - INSERM U1315
Matthew L. Tedder - Greenwood Genetic Center
Monika Weisz Hubshman - Texas Children’s Hospital, Genetic Department
Shamika Ketkar - Department of Molecular and Human Genetics, Baylor College of Medicine
Hongzheng Dai - Department of Molecular and Human Genetics, Baylor College of Medicine
Kim Carlyle Worley - Department of Molecular and Human Genetics, Baylor College of Medicine
Jill A. Rosenfeld - Department of Molecular and Human Genetics, Baylor College of Medicine
Hsiao-Tuan Chao - McNair Medical Institute, The Robert and Janice McNair Foundation
Geoffrey Neale - Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children’s Research Hospital Memphis
Gemma L. Carvill - Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine
Zhaoming Wang - Department of Epidemiology and Cancer Control, St. Jude Children’s Research Hospital
Samuel F. Berkovic - The University of Melbourne
Lynette G. Sadleir - University of Otago
Danny E. Miller - University of Washington
Ingrid E. Scheffer - Murdoch Children's Research Institute
University of Washington Center for Rare Disease Research
Bekim Sadikovic - Verspeeten Clinical Genome Centre, London Health Science Centre
Heather C. Mefford - St. Jude Children's Research Hospital
Détails de publication: medRxiv
Éditeur: Cold Spring Harbor Laboratory Press
Édition: 1.1
Nombre de pages: 55
Identifiants: 99141090509311
Unité académique: Cell souches plasticité cellul régénérat tissulaire immuno des maladies inflamm - IRMB
Langue: English
Type de ressource: Preprint