TY - JOUR
T1 - BAFopathies' DNA methylation epi-signatures demonstrate diagnostic utility and functional continuum of Coffin-Siris and Nicolaides-Baraitser syndromes
AU - Aref-Eshghi, Erfan
AU - Bend, Eric G.
AU - Hood, Rebecca L.
AU - Schenkel, Laila C.
AU - Carere, Deanna Alexis
AU - Chakrabarti, Rana
AU - Nagamani, Sandesh C. S.
AU - Cheung, Sau Wai
AU - Campeau, Philippe M.
AU - Prasad, Chitra
AU - Siu, Victoria Mok
AU - Brady, Lauren
AU - Tarnopolsky, Mark A.
AU - Callen, David J.
AU - Innes, A. Micheil
AU - White, Susan M.
AU - Meschino, Wendy S.
AU - Shuen, Andrew Y.
AU - Paré, Guillaume
AU - Bulman, Dennis E.
AU - Ainsworth, Peter J.
AU - Lin, Hanxin
AU - Rodenhiser, David I.
AU - Hennekam, Raoul C.
AU - Boycott, Kym M.
AU - Schwartz, Charles E.
AU - Sadikovic, Bekim
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85056802476&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/30459321
U2 - https://doi.org/10.1038/s41467-018-07193-y
DO - https://doi.org/10.1038/s41467-018-07193-y
M3 - Article
C2 - 30459321
SN - 2041-1723
VL - 9
SP - 4885
JO - Nature communications
JF - Nature communications
IS - 1
ER -