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

Author

Listed:
  • Christy W. LaFlamme

    (St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital)

  • Cassandra Rastin

    (Western University
    London Health Science Centre)

  • Soham Sengupta

    (St. Jude Children’s Research Hospital)

  • Helen E. Pennington

    (St. Jude Children’s Research Hospital
    Rhodes College)

  • Sophie J. Russ-Hall

    (University of Melbourne, Austin Health)

  • Amy L. Schneider

    (University of Melbourne, Austin Health)

  • Emily S. Bonkowski

    (St. Jude Children’s Research Hospital)

  • Edith P. Almanza Fuerte

    (St. Jude Children’s Research Hospital)

  • Talia J. Allan

    (University of Melbourne, Austin Health)

  • Miranda Perez-Galey Zalusky

    (University of Washington and Seattle Children’s Hospital)

  • Joy Goffena

    (University of Washington and Seattle Children’s Hospital)

  • Sophia B. Gibson

    (University of Washington and Seattle Children’s Hospital
    University of Washington School of Medicine)

  • Denis M. Nyaga

    (University of Otago)

  • Nico Lieffering

    (University of Otago)

  • Malavika Hebbar

    (University of Washington and Seattle Children’s Hospital)

  • Emily V. Walker

    (St. Jude Children’s Research Hospital Memphis)

  • Daniel Darnell

    (St. Jude Children’s Research Hospital Memphis)

  • Scott R. Olsen

    (St. Jude Children’s Research Hospital Memphis)

  • Pandurang Kolekar

    (St. Jude Children’s Research Hospital)

  • Mohamed Nadhir Djekidel

    (St. Jude Children’s Research Hospital)

  • Wojciech Rosikiewicz

    (St. Jude Children’s Research Hospital)

  • Haley McConkey

    (London Health Science Centre)

  • Jennifer Kerkhof

    (London Health Science Centre)

  • Michael A. Levy

    (London Health Science Centre)

  • Raissa Relator

    (London Health Science Centre)

  • Dorit Lev

    (Wolfson Medical Center)

  • Tally Lerman-Sagie

    (Pediatric Neurology Unit, Wolfson Medical Center
    Tel-Aviv University)

  • Kristen L. Park

    (University of Colorado School of Medicine)

  • Marielle Alders

    (Amsterdam UMC, University of Amsterdam, Amsterdam)

  • Gerarda Cappuccio

    (Telethon Institute of Genetics and Medicine
    Federico II University of Naples)

  • Nicolas Chatron

    (University Hospital of Lyon and Claude Bernard Lyon I University
    UCBL, CNRS UMR5261 - INSERM)

  • Leigh Demain

    (Manchester University NHS Foundation Trust, Health Innovation Manchester)

  • David Genevieve

    (CHU Montpellier)

  • Gaetan Lesca

    (University Hospital of Lyon and Claude Bernard Lyon I University
    UCBL, CNRS UMR5261 - INSERM)

  • Tony Roscioli

    (Neuroscience Research Australia (NeuRA)
    University of New South Wales
    Prince of Wales Hospital)

  • Damien Sanlaville

    (University Hospital of Lyon and Claude Bernard Lyon I University
    UCBL, CNRS UMR5261 - INSERM)

  • Matthew L. Tedder

    (Greenwood Genetic Center)

  • Sachin Gupta

    (The Children’s Hospital at Westmead)

  • Elizabeth A. Jones

    (Manchester University NHS Foundation Trust, Health Innovation Manchester
    University of Manchester)

  • Monika Weisz-Hubshman

    (Baylor College of Medicine
    Genetic Department)

  • Shamika Ketkar

    (Baylor College of Medicine)

  • Hongzheng Dai

    (Baylor College of Medicine)

  • Kim C. Worley

    (Baylor College of Medicine)

  • Jill A. Rosenfeld

    (Baylor College of Medicine)

  • Hsiao-Tuan Chao

    (Baylor College of Medicine
    Baylor College of Medicine
    Texas Children’s Hospital
    Texas Children’s Hospital)

  • Geoffrey Neale

    (St. Jude Children’s Research Hospital Memphis)

  • Gemma L. Carvill

    (Northwestern University Feinberg School of Medicine)

  • Zhaoming Wang

    (St. Jude Children’s Research Hospital
    St. Jude Children’s Research Hospital)

  • Samuel F. Berkovic

    (University of Melbourne, Austin Health)

  • Lynette G. Sadleir

    (University of Otago)

  • Danny E. Miller

    (University of Washington and Seattle Children’s Hospital
    University of Washington
    University of Washington)

  • Ingrid E. Scheffer

    (University of Melbourne, Austin Health
    University of Melbourne, Royal Children’s Hospital
    Florey Institute and Murdoch Children’s Research Institute)

  • Bekim Sadikovic

    (Western University
    London Health Science Centre)

  • Heather C. Mefford

    (St. Jude Children’s Research Hospital)

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.

Suggested Citation

  • Christy W. LaFlamme & Cassandra Rastin & Soham Sengupta & Helen E. Pennington & Sophie J. Russ-Hall & Amy L. Schneider & Emily S. Bonkowski & Edith P. Almanza Fuerte & Talia J. Allan & Miranda Perez-G, 2024. "Diagnostic utility of DNA methylation analysis in genetically unsolved pediatric epilepsies and CHD2 episignature refinement," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50159-6
    DOI: 10.1038/s41467-024-50159-6
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