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BAFopathies’ DNA methylation epi-signatures demonstrate diagnostic utility and functional continuum of Coffin–Siris and Nicolaides–Baraitser syndromes

Author

Listed:
  • Erfan Aref-Eshghi

    (Western University
    London Health Sciences Centre)

  • Eric G. Bend

    (Prevention Genetics)

  • Rebecca L. Hood

    (University of Ottawa)

  • Laila C. Schenkel

    (Western University
    London Health Sciences Centre)

  • Deanna Alexis Carere

    (London Health Sciences Centre)

  • Rana Chakrabarti

    (Children’s Health Research Institute)

  • Sandesh C. S. Nagamani

    (Baylor College of Medicine)

  • Sau Wai Cheung

    (Baylor College of Medicine)

  • Philippe M. Campeau

    (University of Montreal)

  • Chitra Prasad

    (Children’s Health Research Institute)

  • Victoria Mok Siu

    (Children’s Health Research Institute)

  • Lauren Brady

    (McMaster University)

  • Mark A. Tarnopolsky

    (McMaster University)

  • David J. Callen

    (McMaster University)

  • A. Micheil Innes

    (University of Calgary)

  • Susan M. White

    (University of Melbourne)

  • Wendy S. Meschino

    (North York General Hospital)

  • Andrew Y. Shuen

    (Children’s Health Research Institute)

  • Guillaume Paré

    (McMaster University)

  • Dennis E. Bulman

    (University of Ottawa)

  • Peter J. Ainsworth

    (Western University
    London Health Sciences Centre)

  • Hanxin Lin

    (Western University
    London Health Sciences Centre)

  • David I. Rodenhiser

    (Children’s Health Research Institute
    Western University)

  • Raoul C. Hennekam

    (University of Amsterdam)

  • Kym M. Boycott

    (University of Ottawa)

  • Charles E. Schwartz

    (Greenwood Genetic Center)

  • Bekim Sadikovic

    (Western University
    London Health Sciences Centre)

Abstract

Coffin–Siris and Nicolaides–Baraitser syndromes (CSS and NCBRS) are Mendelian disorders caused by mutations in subunits of the BAF chromatin remodeling complex. We report overlapping peripheral blood DNA methylation epi-signatures in individuals with various subtypes of CSS (ARID1B, SMARCB1, and SMARCA4) and NCBRS (SMARCA2). We demonstrate that the degree of similarity in the epi-signatures of some CSS subtypes and NCBRS can be greater than that within CSS, indicating a link in the functional basis of the two syndromes. We show that chromosome 6q25 microdeletion syndrome, harboring ARID1B deletions, exhibits a similar CSS/NCBRS methylation profile. Specificity of this epi-signature was confirmed across a wide range of neurodevelopmental conditions including other chromatin remodeling and epigenetic machinery disorders. We demonstrate that a machine-learning model trained on this DNA methylation profile can resolve ambiguous clinical cases, reclassify those with variants of unknown significance, and identify previously undiagnosed subjects through targeted population screening.

Suggested Citation

  • Erfan Aref-Eshghi & Eric G. Bend & Rebecca L. Hood & Laila C. Schenkel & Deanna Alexis Carere & Rana Chakrabarti & Sandesh C. S. Nagamani & Sau Wai Cheung & Philippe M. Campeau & Chitra Prasad & Victo, 2018. "BAFopathies’ DNA methylation epi-signatures demonstrate diagnostic utility and functional continuum of Coffin–Siris and Nicolaides–Baraitser syndromes," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-07193-y
    DOI: 10.1038/s41467-018-07193-y
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    Cited by:

    1. 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.

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