ArticleNature communications2024
Diagnostic utility of DNA methylation analysis in genetically unsolved pediatric epilepsies and CHD2 episignature refinement.
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Article in Nature communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers, 2 of them syntheses that pooled it.
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26citing papers in PubMed, 2 pooled it
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Who cites it
26 citing papers in PubMed, 2 syntheses or guidelines pooled it.
- Paediatric DNA methylation profile scores: a systematic review and open-source atlas.EBioMedicine · 2026Pooled it
- Diagnostic yield of long-read sequencing for rare diseases: a systematic review.Frontiers in genetics · 2026Pooled it
- Clinical Epigenomics in Rare Diseases: Interpreting DNA Methylation Episignatures.Molecular genetics & genomic medicine · 2026Review
- Comprehensive Assessment of the KDM2B-Associated Neurodevelopmental Disorder and the 12q24.31 Microdeletion Syndrome.Clinical genetics · 2026Article
- Structural variant discovery and diagnostic impact in rare diseases from short-read and long-read sequencing.medRxiv : the preprint server for health sciences · 2026Article
- Population-scale detection of methylation outliers from long-read genome sequencing.medRxiv : the preprint server for health sciences · 2026Article
- Long-read genome sequencing improves detection and functional interpretation of structural and repeat variants in autism.Cell genomics · 2026Article
- High-resolution single-cell mapping of clonal hematopoiesis and structural variation in aplastic anemia.Nature genetics · 2026Article
- Genome-wide detection and clinical prioritization of tandem repeat outliers using long-read sequencing.medRxiv : the preprint server for health sciences · 2026Article
- Genome sequencing boosts diagnostic yield for the developmental and epileptic encephalopathies.medRxiv : the preprint server for health sciences · 2026Article
- Lennox-Gastaut syndrome unveiled: Advancing diagnosis, therapies, and advocacy-insights from the Genoa International Workshop.Epilepsia · 2026Review
- Integrating rare and common variation in epilepsy genetics: from genetic architecture to penetrance and clinical expressivity.Frontiers in genetics · 2026Review
- Multiomic Investigation of Shared Genetic Pathways in Paediatric Congenital Heart Disease and Neurodevelopmental Disorders.Human mutation · 2026Article
- Analysis Methods for Diagnosing Rare Neurodevelopmental Diseases with Episignatures: A Systematic Review of the Literature.Biomedicines · 2025Review
- GREGoR: accelerating genomics for rare diseases.Nature · 2025Article
- A CGG Repeat Expansion in CSNK1E Associated with Progressive Myoclonic Epilepsy with Incomplete Penetrance.Movement disorders : official journal of the Movement Disorder Society · 2025Article
- Clinical utility of DNA-methylation signatures in routine diagnostics for neurodevelopmental disorders.European journal of human genetics : EJHG · 2025Article
- CRISPR/Cas12a-Based Biosensing: Advances in Mechanisms and Applications for Nucleic Acid Detection.Biosensors · 2025Review
- Vagus Nerve Stimulation Inhibits DNA and RNA Methylation in a Rat Model of Pilocarpine-Induced Temporal Lobe Epilepsy.CNS neuroscience & therapeutics · 2025Article
- Evolution of genome-wide methylation profiling technologies.Genome research · 2025Review
Corrections and comments
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Authors and funding
56 authors.
Christy W LaFlamme *Center for Pediatric Neurological Disease Research, Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.ORCID http://orcid.org/0000-0002-0808-3475
Cassandra Rastin *Department of Pathology & Laboratory Medicine, Western University, London, ON, N5A 3K7, Canada.ORCID http://orcid.org/0009-0006-7622-2111
Soham SenguptaCenter for Pediatric Neurological Disease Research, Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
Helen E PenningtonCenter for Pediatric Neurological Disease Research, Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.ORCID http://orcid.org/0009-0004-6534-5859
Sophie J Russ-HallEpilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC, 3084, Australia.ORCID http://orcid.org/0000-0002-4809-9340
Amy L SchneiderEpilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC, 3084, Australia.ORCID http://orcid.org/0000-0001-5260-7187
Emily S BonkowskiCenter for Pediatric Neurological Disease Research, Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
Edith P Almanza FuerteCenter for Pediatric Neurological Disease Research, Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
Talia J AllanEpilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC, 3084, Australia.ORCID http://orcid.org/0000-0002-0970-6750
Miranda Perez-Galey ZaluskyDivision of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, WA, 98195, USA.ORCID http://orcid.org/0000-0002-4721-7499
Joy GoffenaDivision of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, WA, 98195, USA.ORCID http://orcid.org/0000-0002-2346-2879
Sophia B GibsonDivision of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, WA, 98195, USA.ORCID http://orcid.org/0000-0001-9839-9045
Denis M NyagaDepartment of Paediatrics and Child Health, University of Otago, Wellington, 6242, New Zealand.ORCID http://orcid.org/0000-0001-6240-4017
Nico LiefferingDepartment of Paediatrics and Child Health, University of Otago, Wellington, 6242, New Zealand.
Malavika HebbarDivision of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, WA, 98195, USA.
Emily V WalkerHartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital Memphis, Memphis, TN, 38105, USA.ORCID http://orcid.org/0000-0003-4880-1483
Daniel DarnellHartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital Memphis, Memphis, TN, 38105, USA.
Scott R OlsenHartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital Memphis, Memphis, TN, 38105, USA.
Pandurang KolekarDepartment of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.ORCID http://orcid.org/0000-0003-0044-0076
Mohamed Nadhir DjekidelCenter for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
Wojciech RosikiewiczCenter for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.ORCID http://orcid.org/0000-0001-7031-3430
Haley McConkeyVerspeeten Clinical Genome Centre, London Health Science Centre, London, ON, N6A 5W9, Canada.
Jennifer KerkhofVerspeeten Clinical Genome Centre, London Health Science Centre, London, ON, N6A 5W9, Canada.ORCID http://orcid.org/0000-0003-1245-6606
Michael A LevyVerspeeten Clinical Genome Centre, London Health Science Centre, London, ON, N6A 5W9, Canada.
Raissa RelatorVerspeeten Clinical Genome Centre, London Health Science Centre, London, ON, N6A 5W9, Canada.
Dorit LevInstitute of Medical Genetics, Wolfson Medical Center, Holon, 58100, Israel.
Tally Lerman-SagieFetal Neurology Clinic, Pediatric Neurology Unit, Wolfson Medical Center, Holon, 58100, Israel.
Kristen L ParkDepartments of Pediatrics and Neurology, University of Colorado School of Medicine, Aurora, CO, 80045, USA.ORCID http://orcid.org/0000-0001-5527-3047
Marielle AldersDepartment of Human Genetics, Amsterdam Reproduction and Development Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, Meibergdreef 9, Amsterdam, Netherlands.ORCID http://orcid.org/0000-0002-7386-4868
Gerarda CappuccioTelethon Institute of Genetics and Medicine, Pozzuoli, Italy.
Nicolas ChatronDepartment of Medical Genetics, Member of the ERN EpiCARE, University Hospital of Lyon and Claude Bernard Lyon I University, Lyon, France.ORCID http://orcid.org/0000-0003-0538-0981
Leigh DemainManchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK.
David GenevieveMontpellier University, Inserm Unit 1183, Reference Center for Rare Diseases Developmental Anomaly and Malformative Syndrome, Clinical Genetic Department, CHU Montpellier, Montpellier, France.ORCID http://orcid.org/0000-0001-6928-6287
Gaetan LescaDepartment of Medical Genetics, Member of the ERN EpiCARE, University Hospital of Lyon and Claude Bernard Lyon I University, Lyon, France.ORCID http://orcid.org/0000-0001-7691-9492
Tony RoscioliNeuroscience Research Australia (NeuRA), Sydney, NSW, Australia.ORCID http://orcid.org/0000-0003-1502-5000
Damien SanlavilleDepartment of Medical Genetics, Member of the ERN EpiCARE, University Hospital of Lyon and Claude Bernard Lyon I University, Lyon, France.
Matthew L TedderGreenwood Genetic Center, Greenwood, SC, 29646, USA.
Sachin GuptaTY Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, Westmead, NSW, Australia.
Elizabeth A JonesManchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK.
Monika Weisz-HubshmanDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
Shamika KetkarDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
Hongzheng DaiDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
Kim C WorleyDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.ORCID http://orcid.org/0000-0002-0282-1000
Jill A RosenfeldDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.ORCID http://orcid.org/0000-0001-5664-7987
Hsiao-Tuan ChaoDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.ORCID http://orcid.org/0000-0002-2854-5470
Undiagnosed Diseases Network
Geoffrey NealeHartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital Memphis, Memphis, TN, 38105, USA.ORCID http://orcid.org/0000-0003-3776-0858
Gemma L CarvillKen and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.ORCID http://orcid.org/0000-0003-4945-3628
University of Washington Center for Rare Disease Research
Zhaoming WangDepartment of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.ORCID http://orcid.org/0000-0001-7556-3869
Samuel F BerkovicEpilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC, 3084, Australia.ORCID http://orcid.org/0000-0003-4580-841X
Lynette G SadleirDepartment of Paediatrics and Child Health, University of Otago, Wellington, 6242, New Zealand.
Danny E MillerDivision of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, WA, 98195, USA.
Ingrid E SchefferEpilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC, 3084, Australia.
Bekim SadikovicDepartment of Pathology & Laboratory Medicine, Western University, London, ON, N5A 3K7, Canada. Bekim.Sadikovic@lhsc.on.ca.ORCID http://orcid.org/0000-0001-6363-0016
Heather C MeffordCenter for Pediatric Neurological Disease Research, Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. Heather.Mefford@stjude.org.ORCID http://orcid.org/0000-0001-7188-522X
Funding
INTERDISCIPLINARY TRAINING IN GENOMIC SCIENCEST32HG000035 · NHGRI · UNIVERSITY OF WASHINGTON · PI Bruce Colston Trapnell · 1995 to 2026
$24.2MUniversity of Washington Mendelian Genomics Research Center (UW-MGRC)U01HG011744 · NHGRI · UNIVERSITY OF WASHINGTON · PI MICHAEL Joseph BAMSHAD, Evan Eichler · 2021 to 2026
$15.8MUW Center for Mendelian GenomicsUM1HG006493 · NHGRI · UNIVERSITY OF WASHINGTON · PI BAMSHAD, MICHAEL JOSEPH, LEAL, SUZANNE M · 2016 to 2020
$15.3MUniversity of Washington (UW) Mendelian Genomics Data Coordinating CenterU24HG011746 · NHGRI · UNIVERSITY OF WASHINGTON · PI Susanne May, ALI SHOJAIE · 2021 to 2026
$14.8MPilot of New Technologies to Increase the Genomic Diagnosis of Undiagnosed Disease Network (UDN) PatientsU01HG007709 · NHGRI · BAYLOR COLLEGE OF MEDICINE · PI BACINO, CARLOS A., LEE, BRENDAN · 2014 to 2022
$14.3MClinical Sequencing Core Facility for the Undiagnosed Diseases Network (UDN)U01HG007942 · NHGRI · BAYLOR COLLEGE OF MEDICINE · PI ENG, CHRISTINE · 2014 to 2021
$10.2MUrine-Derived Cell RNA Sequencing to Improve Diagnosis in Undiagnosed UDN Participants.U01NS134348 · NINDS · BAYLOR COLLEGE OF MEDICINE · PI Carlos A. Bacino, Brendan Lee · 2023 to 2026
$3.8MPacific Northwest Undiagnosed Diseases Network Clinical SiteU01NS134355 · NINDS · UNIVERSITY OF WASHINGTON · PI ELIZABETH ELOYCE BLUE, Katrina M Dipple · 2023 to 2026
$3.0MLong-read DNA and RNA sequencing to identify disease-causing genetic variation and streamline testingDP5OD033357 · OD · UNIVERSITY OF WASHINGTON · PI MILLER, DANNY ERWIN · 2022 to 2025
$1.9MNHGRI NIH HHS T32 HG000035NHGRI NIH HHS U01 HG007709NHGRI NIH HHS U01 HG007942NHGRI NIH HHS U01 HG011744NHGRI NIH HHS U24 HG011746NHGRI NIH HHS UM1 HG006493NIH HHS DP5 OD033357NINDS NIH HHS U01 NS134348NINDS NIH HHS U01 NS134355
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.
Indexed as
DNA Copy Number VariationsDNA MethylationEpilepsyAdolescentChildChild, PreschoolDNA-Binding ProteinsFemaleGenetic TestingHumansInfantMaleCHD2 protein, humanDNA-Binding Proteins
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