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

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, Victoria Mok Siu, Lauren Brady, Mark A. Tarnopolsky, David J. Callen, A. Micheil Innes, Susan M. White, Wendy S. Meschino, Andrew Y. Shuen, Guillaume Paré, Dennis E. Bulman, Peter J. Ainsworth, Hanxin Lin, David I. Rodenhiser, Raoul C. Hennekam, Kym M. Boycott, Charles E. Schwartz and Bekim Sadikovic ()
Additional contact information
Erfan Aref-Eshghi: Western University
Eric G. Bend: Prevention Genetics
Rebecca L. Hood: University of Ottawa
Laila C. Schenkel: Western University
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
Hanxin Lin: Western University
David I. Rodenhiser: Children’s Health Research Institute
Raoul C. Hennekam: University of Amsterdam
Kym M. Boycott: University of Ottawa
Charles E. Schwartz: Greenwood Genetic Center
Bekim Sadikovic: Western University

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-07193-y

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