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Start Over Author "Kolekar P" Publication Type Electronic Resources
2 results on '"Kolekar P"'

1. Diagnostic utility of DNA methylation analysis in genetically unsolved pediatric epilepsies and CHD2 episignature refinement

Author

LaFlamme, CW, Rastin, C, Sengupta, S, Pennington, HE, Russ-Hall, SJ, Schneider, AL, Bonkowski, ES, Almanza Fuerte, EP, Allan, TJ, Zalusky, MP-G, Goffena, J, Gibson, SB, Nyaga, DM, Lieffering, N, Hebbar, M, Walker, EV, Darnell, D, Olsen, SR, Kolekar, P, Djekidel, MN, Rosikiewicz, W, McConkey, H, Kerkhof, J, Levy, MA, Relator, R, Lev, D, Lerman-Sagie, T, Park, KL, Alders, M, Cappuccio, G, Chatron, N, Demain, L, Genevieve, D, Lesca, G, Roscioli, T, Sanlaville, D, Tedder, ML, Gupta, S, Jones, EA, Weisz-Hubshman, M, Ketkar, S, Dai, H, Worley, KC, Rosenfeld, JA, Chao, H-T, Undiagnosed Diseases Network, Neale, G, Carvill, GL, University of Washington Center for Rare Disease Research, Wang, Z, Berkovic, SF, Sadleir, LG, Miller, DE, Scheffer, IE, Sadikovic, B, Mefford, HC, LaFlamme, CW, Rastin, C, Sengupta, S, Pennington, HE, Russ-Hall, SJ, Schneider, AL, Bonkowski, ES, Almanza Fuerte, EP, Allan, TJ, Zalusky, MP-G, Goffena, J, Gibson, SB, Nyaga, DM, Lieffering, N, Hebbar, M, Walker, EV, Darnell, D, Olsen, SR, Kolekar, P, Djekidel, MN, Rosikiewicz, W, McConkey, H, Kerkhof, J, Levy, MA, Relator, R, Lev, D, Lerman-Sagie, T, Park, KL, Alders, M, Cappuccio, G, Chatron, N, Demain, L, Genevieve, D, Lesca, G, Roscioli, T, Sanlaville, D, Tedder, ML, Gupta, S, Jones, EA, Weisz-Hubshman, M, Ketkar, S, Dai, H, Worley, KC, Rosenfeld, JA, Chao, H-T, Undiagnosed Diseases Network, Neale, G, Carvill, GL, University of Washington Center for Rare Disease Research, Wang, Z, Berkovic, SF, Sadleir, LG, Miller, DE, Scheffer, IE, Sadikovic, B, and Mefford, HC

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.

Published
2024

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

Author

LaFlamme, CW, Rastin, C, Sengupta, S, Pennington, HE, Russ-Hall, SJ, Schneider, AL, Bonkowski, ES, Almanza Fuerte, EP, Galey, M, Goffena, J, Gibson, SB, Allan, TJ, Nyaga, DM, Lieffering, N, Hebbar, M, Walker, EV, Darnell, D, Olsen, SR, Kolekar, P, Djekidel, N, Rosikiewicz, W, McConkey, H, Kerkhof, J, Levy, MA, Relator, R, Lev, D, Lerman-Sagie, T, Park, KL, Alders, M, Cappuccio, G, Chatron, N, Demain, L, Genevieve, D, Lesca, G, Roscioli, T, Sanlaville, D, Tedder, ML, Hubshman, MW, Ketkar, S, Dai, H, Worley, KC, Rosenfeld, JA, Chao, H-T, Undiagnosed Diseases Network, Neale, G, Carvill, GL, University of Washington Center for Rare Disease Research, Wang, Z, Berkovic, SF, Sadleir, LG, Miller, DE, Scheffer, IE, Sadikovic, B, Mefford, HC, LaFlamme, CW, Rastin, C, Sengupta, S, Pennington, HE, Russ-Hall, SJ, Schneider, AL, Bonkowski, ES, Almanza Fuerte, EP, Galey, M, Goffena, J, Gibson, SB, Allan, TJ, Nyaga, DM, Lieffering, N, Hebbar, M, Walker, EV, Darnell, D, Olsen, SR, Kolekar, P, Djekidel, N, Rosikiewicz, W, McConkey, H, Kerkhof, J, Levy, MA, Relator, R, Lev, D, Lerman-Sagie, T, Park, KL, Alders, M, Cappuccio, G, Chatron, N, Demain, L, Genevieve, D, Lesca, G, Roscioli, T, Sanlaville, D, Tedder, ML, Hubshman, MW, Ketkar, S, Dai, H, Worley, KC, Rosenfeld, JA, Chao, H-T, Undiagnosed Diseases Network, Neale, G, Carvill, GL, University of Washington Center for Rare Disease Research, Wang, Z, Berkovic, SF, Sadleir, LG, Miller, DE, Scheffer, IE, Sadikovic, B, and Mefford, HC

Abstract

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.

Published
2023

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