BAFopathies’ DNA methylation epi-signatures demonstrate diagnostic utility and functional continuum of Coffin–Siris and Nicolaides–Baraitser syndromes
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2018-12-01
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Nature Communications
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NATURE PUBLISHING GROUP
Melbourne Authors
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Paediatrics (RCH)
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Journal Article
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Aref-Eshghi, E., Bend, E. G., Hood, R. L., Schenkel, L. C., Carere, D. A., Chakrabarti, R., Nagamani, S. C. S., Cheung, S. W., Campeau, P. M., Prasad, C., Siu, V. M., Brady, L., Tarnopolsky, M. A., Callen, D. J., Innes, A. M., White, S. M., Meschino, W. S., Shuen, A. Y., Paré, G. ,... Sadikovic, B. (2018). BAFopathies’ DNA methylation epi-signatures demonstrate diagnostic utility and functional continuum of Coffin–Siris and Nicolaides–Baraitser syndromes. Nature Communications, 9 (1), https://doi.org/10.1038/s41467-018-07193-y.
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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.