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, Geoffrey Neale, Gemma L. Carvill, Zhaoming Wang, Samuel F. Berkovic, Lynette G. Sadleir, Danny E. Miller, Ingrid E. Scheffer, Bekim Sadikovic () and Heather C. Mefford ()
Additional contact information
Christy W. LaFlamme: St. Jude Children’s Research Hospital
Cassandra Rastin: Western University
Soham Sengupta: St. Jude Children’s Research Hospital
Helen E. Pennington: St. Jude Children’s Research Hospital
Sophie J. Russ-Hall: University of Melbourne, Austin Health
Amy L. Schneider: University of Melbourne, Austin Health
Emily S. Bonkowski: St. Jude Children’s Research Hospital
Edith P. Almanza Fuerte: St. Jude Children’s Research Hospital
Talia J. Allan: University of Melbourne, Austin Health
Miranda Perez-Galey Zalusky: University of Washington and Seattle Children’s Hospital
Joy Goffena: University of Washington and Seattle Children’s Hospital
Sophia B. Gibson: University of Washington and Seattle Children’s Hospital
Denis M. Nyaga: University of Otago
Nico Lieffering: University of Otago
Malavika Hebbar: University of Washington and Seattle Children’s Hospital
Emily V. Walker: St. Jude Children’s Research Hospital Memphis
Daniel Darnell: St. Jude Children’s Research Hospital Memphis
Scott R. Olsen: St. Jude Children’s Research Hospital Memphis
Pandurang Kolekar: St. Jude Children’s Research Hospital
Mohamed Nadhir Djekidel: St. Jude Children’s Research Hospital
Wojciech Rosikiewicz: St. Jude Children’s Research Hospital
Haley McConkey: London Health Science Centre
Jennifer Kerkhof: London Health Science Centre
Michael A. Levy: London Health Science Centre
Raissa Relator: London Health Science Centre
Dorit Lev: Wolfson Medical Center
Tally Lerman-Sagie: Pediatric Neurology Unit, Wolfson Medical Center
Kristen L. Park: University of Colorado School of Medicine
Marielle Alders: Amsterdam UMC, University of Amsterdam, Amsterdam
Gerarda Cappuccio: Telethon Institute of Genetics and Medicine
Nicolas Chatron: University Hospital of Lyon and Claude Bernard Lyon I University
Leigh Demain: Manchester University NHS Foundation Trust, Health Innovation Manchester
David Genevieve: CHU Montpellier
Gaetan Lesca: University Hospital of Lyon and Claude Bernard Lyon I University
Tony Roscioli: Neuroscience Research Australia (NeuRA)
Damien Sanlaville: University Hospital of Lyon and Claude Bernard Lyon I University
Matthew L. Tedder: Greenwood Genetic Center
Sachin Gupta: The Children’s Hospital at Westmead
Elizabeth A. Jones: Manchester University NHS Foundation Trust, Health Innovation Manchester
Monika Weisz-Hubshman: Baylor College of Medicine
Shamika Ketkar: Baylor College of Medicine
Hongzheng Dai: Baylor College of Medicine
Kim C. Worley: Baylor College of Medicine
Jill A. Rosenfeld: Baylor College of Medicine
Hsiao-Tuan Chao: Baylor College of Medicine
Geoffrey Neale: St. Jude Children’s Research Hospital Memphis
Gemma L. Carvill: Northwestern University Feinberg School of Medicine
Zhaoming Wang: St. Jude Children’s Research Hospital
Samuel F. Berkovic: University of Melbourne, Austin Health
Lynette G. Sadleir: University of Otago
Danny E. Miller: University of Washington and Seattle Children’s Hospital
Ingrid E. Scheffer: University of Melbourne, Austin Health
Bekim Sadikovic: Western University
Heather C. Mefford: St. Jude Children’s Research Hospital

Nature Communications, 2024, vol. 15, issue 1, 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.

Date: 2024
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DOI: 10.1038/s41467-024-50159-6

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