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

Author:

LaFlamme Christy W.ORCID,Rastin CassandraORCID,Sengupta Soham,Pennington Helen E.ORCID,Russ-Hall Sophie J.ORCID,Schneider Amy L.ORCID,Bonkowski Emily S.,Almanza Fuerte Edith P.,Allan Talia J.ORCID,Zalusky Miranda Perez-GaleyORCID,Goffena JoyORCID,Gibson Sophia B.ORCID,Nyaga Denis M.ORCID,Lieffering Nico,Hebbar Malavika,Walker Emily V.ORCID,Darnell Daniel,Olsen Scott R.,Kolekar PandurangORCID,Djekidel Mohamed Nadhir,Rosikiewicz WojciechORCID,McConkey Haley,Kerkhof JenniferORCID,Levy Michael A.,Relator Raissa,Lev Dorit,Lerman-Sagie Tally,Park Kristen L.ORCID,Alders MarielleORCID,Cappuccio Gerarda,Chatron NicolasORCID,Demain Leigh,Genevieve DavidORCID,Lesca GaetanORCID,Roscioli TonyORCID,Sanlaville Damien,Tedder Matthew L.,Gupta Sachin,Jones Elizabeth A.,Weisz-Hubshman Monika,Ketkar Shamika,Dai Hongzheng,Worley Kim C.ORCID,Rosenfeld Jill A.ORCID,Chao Hsiao-TuanORCID, ,Neale GeoffreyORCID,Carvill Gemma L.ORCID, ,Wang ZhaomingORCID,Berkovic Samuel F.ORCID,Sadleir Lynette G.,Miller Danny E.,Scheffer Ingrid E.,Sadikovic BekimORCID,Mefford Heather C.ORCID

Abstract

AbstractSequence-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.

Funder

Citizens United for Research in Epilepsy

Publisher

Springer Science and Business Media LLC

Cited by 1 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. Developmental and epileptic encephalopathies;Nature Reviews Disease Primers;2024-09-05

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3