Nature Communications (Aug 2024)
Diagnostic utility of DNA methylation analysis in genetically unsolved pediatric epilepsies and CHD2 episignature refinement
- Christy W. LaFlamme,
- Cassandra Rastin,
- Soham Sengupta,
- Helen E. Pennington,
- Sophie J. Russ-Hall,
- Amy L. Schneider,
- Emily S. Bonkowski,
- Edith P. Almanza Fuerte,
- Talia J. Allan,
- Miranda Perez-Galey Zalusky,
- Joy Goffena,
- Sophia B. Gibson,
- Denis M. Nyaga,
- Nico Lieffering,
- Malavika Hebbar,
- Emily V. Walker,
- Daniel Darnell,
- Scott R. Olsen,
- Pandurang Kolekar,
- Mohamed Nadhir 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,
- Sachin Gupta,
- Elizabeth A. Jones,
- Monika Weisz-Hubshman,
- Shamika Ketkar,
- Hongzheng Dai,
- Kim C. Worley,
- Jill A. Rosenfeld,
- Hsiao-Tuan Chao,
- Undiagnosed Diseases Network,
- Geoffrey Neale,
- Gemma L. Carvill,
- University of Washington Center for Rare Disease Research,
- Zhaoming Wang,
- Samuel F. Berkovic,
- Lynette G. Sadleir,
- Danny E. Miller,
- Ingrid E. Scheffer,
- Bekim Sadikovic,
- Heather C. Mefford
Affiliations
- Christy W. LaFlamme
- Center for Pediatric Neurological Disease Research, Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital
- Cassandra Rastin
- Department of Pathology & Laboratory Medicine, Western University
- Soham Sengupta
- Center for Pediatric Neurological Disease Research, Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital
- Helen E. Pennington
- Center for Pediatric Neurological Disease Research, Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital
- Sophie J. Russ-Hall
- Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health
- Amy L. Schneider
- Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health
- Emily S. Bonkowski
- Center for Pediatric Neurological Disease Research, Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital
- Edith P. Almanza Fuerte
- Center for Pediatric Neurological Disease Research, Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital
- Talia J. Allan
- Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health
- Miranda Perez-Galey Zalusky
- 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
- Division of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children’s Hospital
- 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
- Mohamed Nadhir 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
- Institute of Medical Genetics, Wolfson Medical Center
- Tally Lerman-Sagie
- Fetal Neurology Clinic, Pediatric Neurology Unit, Wolfson Medical Center
- Kristen L. Park
- Departments of Pediatrics and Neurology, University of Colorado School of Medicine
- Marielle Alders
- Department of Human Genetics, Amsterdam Reproduction and Development Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam
- Gerarda Cappuccio
- Telethon Institute of Genetics and Medicine
- Nicolas Chatron
- Department of Medical Genetics, Member of the ERN EpiCARE, University Hospital of Lyon and Claude Bernard Lyon I University
- Leigh Demain
- Manchester Centre for Genomic Medicine, St Mary’s Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester
- David Genevieve
- Montpellier University, Inserm Unit 1183, Reference Center for Rare Diseases Developmental Anomaly and Malformative Syndrome, Clinical Genetic Department, CHU Montpellier
- Gaetan Lesca
- Department of Medical Genetics, Member of the ERN EpiCARE, University Hospital of Lyon and Claude Bernard Lyon I University
- Tony Roscioli
- Neuroscience Research Australia (NeuRA)
- Damien Sanlaville
- Department of Medical Genetics, Member of the ERN EpiCARE, University Hospital of Lyon and Claude Bernard Lyon I University
- Matthew L. Tedder
- Greenwood Genetic Center
- Sachin Gupta
- TY Nelson Department of Neurology and Neurosurgery, The Children’s Hospital at Westmead
- Elizabeth A. Jones
- Manchester Centre for Genomic Medicine, St Mary’s Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester
- Monika Weisz-Hubshman
- Department of Molecular and Human Genetics, Baylor College of Medicine
- 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 C. 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
- Department of Molecular and Human Genetics, Baylor College of Medicine
- Undiagnosed Diseases Network
- 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
- University of Washington Center for Rare Disease Research
- Zhaoming Wang
- Department of Computational Biology, St. Jude Children’s Research Hospital
- Samuel F. Berkovic
- Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health
- Lynette G. Sadleir
- Department of Paediatrics and Child Health, University of Otago
- Danny E. Miller
- Division of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children’s Hospital
- Ingrid E. Scheffer
- Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health
- Bekim Sadikovic
- Department of Pathology & Laboratory Medicine, Western University
- Heather C. Mefford
- Center for Pediatric Neurological Disease Research, Department of Cell and Molecular Biology, St. Jude Children’s Research Hospital
- DOI
- https://doi.org/10.1038/s41467-024-50159-6
- Journal volume & issue
-
Vol. 15,
no. 1
pp. 1 – 21
Abstract
Abstract Sequence-based genetic testing identifies causative 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. We interrogate the diagnostic utility of genome-wide DNA methylation array analysis on peripheral blood samples from 582 individuals with genetically unsolved DEEs. We identify rare differentially methylated regions (DMRs) and explanatory episignatures to uncover causative and candidate genetic etiologies in 12 individuals. Using long-read sequencing, we identify DNA variants underlying rare DMRs, including one balanced translocation, three CG-rich repeat expansions, and four copy number variants. We also identify pathogenic variants associated with episignatures. Finally, we refine the CHD2 episignature using an 850 K methylation array and 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 variants as 2% (12/582) for unsolved DEE cases.
