TY - JOUR
T1 - Diagnostic utility of DNA methylation analysis in genetically unsolved pediatric epilepsies and CHD2 episignature refinement
AU - Undiagnosed Diseases Network
AU - University of Washington Center for Rare Disease Research
AU - LaFlamme, Christy W.
AU - Rastin, Cassandra
AU - Sengupta, Soham
AU - Pennington, Helen E.
AU - Russ-Hall, Sophie J.
AU - Schneider, Amy L.
AU - Bonkowski, Emily S.
AU - Almanza Fuerte, Edith P.
AU - Allan, Talia J.
AU - Zalusky, Miranda Perez Galey
AU - Goffena, Joy
AU - Gibson, Sophia B.
AU - Nyaga, Denis M.
AU - Lieffering, Nico
AU - Hebbar, Malavika
AU - Walker, Emily V.
AU - Darnell, Daniel
AU - Olsen, Scott R.
AU - Kolekar, Pandurang
AU - Djekidel, Mohamed Nadhir
AU - Rosikiewicz, Wojciech
AU - McConkey, Haley
AU - Kerkhof, Jennifer
AU - Levy, Michael A.
AU - Relator, Raissa
AU - Lev, Dorit
AU - Lerman-Sagie, Tally
AU - Park, Kristen L.
AU - Alders, Marielle
AU - Cappuccio, Gerarda
AU - Chatron, Nicolas
AU - Demain, Leigh
AU - Genevieve, David
AU - Lesca, Gaetan
AU - Roscioli, Tony
AU - Sanlaville, Damien
AU - Tedder, Matthew L.
AU - Gupta, Sachin
AU - Jones, Elizabeth A.
AU - Weisz-Hubshman, Monika
AU - Ketkar, Shamika
AU - Dai, Hongzheng
AU - Worley, Kim C.
AU - Rosenfeld, Jill A.
AU - Chao, Hsiao Tuan
AU - Neale, Geoffrey
AU - Carvill, Gemma L.
AU - Wang, Zhaoming
AU - Berkovic, Samuel F.
AU - Sadleir, Lynette G.
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/12
Y1 - 2024/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85200828171&partnerID=8YFLogxK
U2 - 10.1038/s41467-024-50159-6
DO - 10.1038/s41467-024-50159-6
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C2 - 39107278
AN - SCOPUS:85200828171
SN - 2041-1723
VL - 15
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 6524
ER -