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

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  • AbstractCoffin–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.


  • Aref-Eshghi, Erfan
  • Bend, Eric G
  • Hood, Rebecca L
  • Schenkel, Laila C
  • Carere, Deanna Alexis
  • Chakrabarti, Rana
  • Nagamani, Sandesh CS
  • Cheung, Sau Wai
  • Campeau, Philippe M
  • Prasad, Chitra
  • Siu, Victoria Mok
  • Brady, Lauren
  • Tarnopolsky, Mark
  • Callen, David
  • Innes, A Micheil
  • White, Susan M
  • Meschino, Wendy S
  • Shuen, Andrew Y
  • Pare, Guillaume
  • Bulman, Dennis E
  • Ainsworth, Peter J
  • Lin, Hanxin
  • Rodenhiser, David I
  • Hennekam, Raoul C
  • Boycott, Kym M
  • Schwartz, Charles E
  • Sadikovic, Bekim

publication date

  • November 20, 2018

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