1. BAFopathies' DNA methylation epi-signatures demonstrate diagnostic utility and functional continuum of Coffin-Siris and Nicolaides-Baraitser syndromes
- Author
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Aref-Eshghi, E, Bend, EG, Hood, RL, Schenkel, LC, Carere, DA, Chakrabarti, R, Nagamani, SCS, Cheung, SW, Campeau, PM, Prasad, C, Siu, VM, Brady, L, Tarnopolsky, MA, Callen, DJ, Innes, AM, White, SM, Meschino, WS, Shuen, AY, Pare, G, Bulman, DE, Ainsworth, PJ, Lin, H, Rodenhiser, DI, Hennekam, RC, Boycott, KM, Schwartz, CE, Sadikovic, B, Aref-Eshghi, E, Bend, EG, Hood, RL, Schenkel, LC, Carere, DA, Chakrabarti, R, Nagamani, SCS, Cheung, SW, Campeau, PM, Prasad, C, Siu, VM, Brady, L, Tarnopolsky, MA, Callen, DJ, Innes, AM, White, SM, Meschino, WS, Shuen, AY, Pare, G, Bulman, DE, Ainsworth, PJ, Lin, H, Rodenhiser, DI, Hennekam, RC, Boycott, KM, Schwartz, CE, and Sadikovic, B
- 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.
- Published
- 2018