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

Erfan Aref-Eshghi; Eric G Bend; Rebecca L Hood; Laila C Schenkel; Deanna Alexis Carere; Rana Chakrabarti; Sandesh C S Nagamani; Sau Wai Cheung; Philippe M Campeau; Chitra Prasad; Victoria Mok Siu; Lauren Brady; Mark A Tarnopolsky; David J Callen; A Micheil Innes; Susan M White; Wendy S Meschino; Andrew Y Shuen; Guillaume Paré; Dennis E Bulman; Peter J Ainsworth; Hanxin Lin; David I Rodenhiser; Raoul C Hennekam; Kym M Boycott; Charles E Schwartz; Bekim Sadikovic

doi:10.1038/s41467-018-07193-y

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

Nat Commun. 2018 Nov 20;9(1):4885. doi: 10.1038/s41467-018-07193-y.

Authors

Erfan Aref-Eshghi^{1

2}, Eric G Bend³, Rebecca L Hood⁴, Laila C Schenkel^{1

2}, Deanna Alexis Carere², Rana Chakrabarti⁵, Sandesh C S Nagamani⁶, Sau Wai Cheung⁶, Philippe M Campeau⁷, Chitra Prasad⁵, Victoria Mok Siu⁵, Lauren Brady⁸, Mark A Tarnopolsky⁸, David J Callen⁸, A Micheil Innes⁹, Susan M White¹⁰, Wendy S Meschino¹¹, Andrew Y Shuen⁵, Guillaume Paré¹², Dennis E Bulman⁴, Peter J Ainsworth^{1

2}, Hanxin Lin^{1

2}, David I Rodenhiser^{5

13}, Raoul C Hennekam¹⁴, Kym M Boycott⁴, Charles E Schwartz¹⁵, Bekim Sadikovic^{16

17}

Affiliations

¹ Department of Pathology and Laboratory Medicine, Western University, London, N6A 5W9, ON, Canada.
² Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, N6A 5W9, ON, Canada.
³ Prevention Genetics, Marshfield, 54449, WI, USA.
⁴ Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, K1H 8L1, ON, Canada.
⁵ Children's Health Research Institute, London, N6A 5W9, ON, Canada.
⁶ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, 77030, TX, USA.
⁷ Department of Pediatrics, University of Montreal, Montreal, H3C 3J7, QC, Canada.
⁸ Department of Pediatrics, McMaster University, Hamilton, L8P 1A2, ON, Canada.
⁹ Department of Medical Genetics, Alberta Children's Hospital Research Institute for Child and Maternal Health, University of Calgary, Calgary, T3B 6A8, AB, Canada.
¹⁰ Department of Paediatrics, University of Melbourne, Melbourne, 3052, VIC, Australia.
¹¹ Genetics Program, North York General Hospital, Toronto, M2K 1E1, ON, Canada.
¹² Department of Pathology and Molecular Medicine, McMaster University, Hamilton, L8P 1A2, ON, Canada.
¹³ Department of Pediatrics, Biochemistry and Oncology, Western University, London, N6A 5W9, ON, Canada.
¹⁴ Department of Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, 1012 WX, The Netherlands.
¹⁵ Greenwood Genetic Center, Greenwood, 29646, SC, USA.
¹⁶ Department of Pathology and Laboratory Medicine, Western University, London, N6A 5W9, ON, Canada. Bekim.Sadikovic@lhsc.on.ca.
¹⁷ Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, N6A 5W9, ON, Canada. Bekim.Sadikovic@lhsc.on.ca.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Abnormalities, Multiple / diagnosis
Abnormalities, Multiple / genetics*
Chromatin Assembly and Disassembly
Chromosomal Proteins, Non-Histone / genetics*
DNA Helicases / genetics
DNA Methylation*
DNA-Binding Proteins / genetics
Epigenesis, Genetic
Epigenomics
Face / abnormalities
Facies
Foot Deformities, Congenital / diagnosis
Foot Deformities, Congenital / genetics
Hand Deformities, Congenital / diagnosis
Hand Deformities, Congenital / genetics
Humans
Hypotrichosis / diagnosis
Hypotrichosis / genetics
Intellectual Disability / diagnosis
Intellectual Disability / genetics
Micrognathism / diagnosis
Micrognathism / genetics
Mutation
Neck / abnormalities
Nuclear Proteins / genetics
SMARCB1 Protein / genetics
Syndrome
Transcription Factors / genetics*

Substances

ARID1B protein, human
Chromosomal Proteins, Non-Histone
DNA-Binding Proteins
Nuclear Proteins
SMARCA2 protein, human
SMARCB1 Protein
SMARCB1 protein, human
SWI-SNF-B chromatin-remodeling complex
Transcription Factors
SMARCA4 protein, human
DNA Helicases

Supplementary concepts

Coffin-Siris syndrome
Nicolaides Baraitser syndrome