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

Authors：Aref-Eshghi Erfan; Bend Eric G; Hood Rebecca L; Schenkel Laila C; Carere Deanna Alexis; Chakrabarti Rana; Nagamani Sandesh C S; Cheung Sau Wai; Campeau Philippe M; Pra*** Chitra; Siu Victoria Mok; Brady Lauren; Tarnopolsky Mark A; Callen David J; 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^*

Source：Nature Communications, 2018, 9(1): 4885-4885.

DOI：10.1038/s41467-018-07193-y

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.

• Institution
  6; 2; BAYLOR COLLEGE OF MEDICINE; University of Montreal; Academic Medical Center, University of Amsterdam; The University of Calgary; Baylor college of medicine; bpotest; Baylor college of Medicine; university of ottawa; McMaster university; 1; University of calgary