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 Russ-Hall, Amy Schneider, Emily Bonkowski, Edith P. Almanza Fuerte, Talia J. Allan, Miranda Galey, Joy Goffena, Sophia B Gibson, Denis M. Nyaga, Nico Lieffering, Malavika Hebbar, Emily 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 Park, Mariëlle Alders, Gerarda Cappuccio, Nicolas Chatron, Leigh Demain, David Geneviève, Gaëtan 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, Zhaoming Wang, Samuel F. Berkovic, Lynette G. Sadleir, Danny E. Miller, Ingrid E. Scheffer, Bekim Sadiković, Heather C. Mefford
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.