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

Nat Commun 2018 11 20;9(1):4885. Epub 2018 Nov 20.

Department of Pathology and Laboratory Medicine, Western University, London, N6A 5W9, ON, Canada.

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.

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http://dx.doi.org/10.1038/s41467-018-07193-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6244416PMC
November 2018
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References

(Supplied by CrossRef)

GW Santen et al.
Epigenetics 2012

GS Coffin et al.
Am. J. Dis. Child. 1970

JK Houdt Van et al.
Nat. Genet. 2012

D Wieczorek et al.
Hum. Mol. Genet. 2013

P Nicolaides et al.
Clin. Dermatol. 1993

G Vasileiou et al.
Am. J. Hum. Genet. 2018

Y Tsurusaki et al.
Clin. Genet. 2014

Y Tsurusaki et al.
Nat. Commun. 2014

H Cedar et al.
Nat. Rev. Genet. 2009

J Datta et al.
Cancer Res. 2005

L Ho et al.
Proc. Natl. Acad. Sci. USA 2009

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