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BMC Med Genomics. 2019 Jul 9;12(1):105. doi: 10.1186/s12920-019-0555-y.

New insights into DNA methylation signatures: SMARCA2 variants in Nicolaides-Baraitser syndrome.

Author information

1
Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada.
2
Division of Genetics, Department of Pediatrics, McMaster University, Hamilton, Ontario, L8S 4L8, Canada.
3
Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada.
4
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, M5S 1A1, Canada.
5
Centre for Computational Medicine, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada.
6
Department of Genetic Medicine, Munroe-Meyer Institute, University of Nebraska Medical Center, Omaha, NE, USA.
7
Genetics Program, North York General Hospital, Toronto, Ontario, M2K 1E1, Canada.
8
Department of Paediatrics, University of Toronto, Toronto, Ontario, M5S 3H7, Canada.
9
Department of Pediatrics, UCLA, Los Angeles, CA, 90095, USA.
10
Division of Clinical Genetics, Children's Mercy Hospital, Kansas City, MO, 66111, USA.
11
Division of Pediatric Clinical Genetics, University of Utah School of Medicine, Salt Lake City, UT, 84132, USA.
12
Service de génétique clinique, Département de génétique médicale, maladies rares, médecine personnalisée, Unité INSERM U1183, Université Montpellier, CHU Montpellier, 34000, Montpellier, France.
13
Department of Pediatrics, University of Toronto, Toronto, Ontario, M5S 1A1, Canada.
14
AP-HP, Department of Genetics, Hôpital Robert Debré, 75019, Paris, France.
15
University of Missouri Kansas City, School of Medicine, Kansas City, MO, 64108, USA.
16
Division of Clinical Genetics, Children's Mercy Hospital, Kansas City, MO, 64108, USA.
17
Department of Pediatrics, Children's Mercy Hospital, Kansas City, MO, 64108, USA.
18
Department of Health, Government of Western Australia, Genetic Services of Western Australia, Perth, WA, Australia.
19
The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada.
20
McLaughlin Centre, University of Toronto, Toronto, Ontario, M5S 1A1, Canada.
21
Holland Bloorview Kids Rehabilitation Hospital Toronto, Toronto, Ontario, M4G 1R8, Canada.
22
Institute of Medical Science, University of Toronto, Toronto, Ontario, M5S 1A1, Canada.
23
Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67400, Illkirch, France.
24
Laboratoire de Diagnostic Génétique, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, 67000, Strasbourg, France.
25
Division of Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA.
26
The Department of Pediatrics, The Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, 19104, USA.
27
Department of Computer Science, University of Toronto, Toronto, Ontario, M5S 1A1, Canada.
28
Prenatal Diagnosis and Medical Genetics Program, Mount Sinai Hospital, Toronto, Ontario, M5G 1X5, Canada.
29
Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada. rweksb@sickkids.ca.
30
Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada. rweksb@sickkids.ca.
31
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, M5S 1A1, Canada. rweksb@sickkids.ca.
32
Institute of Medical Sciences, University of Toronto, Toronto, Ontario, M5S 1A8, Canada. rweksb@sickkids.ca.

Abstract

BACKGROUND:

Nicolaides-Baraitser syndrome (NCBRS) is a neurodevelopmental disorder caused by pathogenic sequence variants in SMARCA2 which encodes the catalytic component of the chromatin remodeling BAF complex. Pathogenic variants in genes that encode epigenetic regulators have been associated with genome-wide changes in DNA methylation (DNAm) in affected individuals termed DNAm signatures.

METHODS:

Genome-wide DNAm was assessed in whole-blood samples from the individuals with pathogenic SMARCA2 variants and NCBRS diagnosis (n = 8) compared to neurotypical controls (n = 23) using the Illumina MethylationEPIC array. Differential methylated CpGs between groups (DNAm signature) were identified and used to generate a model enabling classification variants of uncertain significance (VUS; n = 9) in SMARCA2 as "pathogenic" or "benign". A validation cohort of NCBRS cases (n = 8) and controls (n = 96) demonstrated 100% model sensitivity and specificity.

RESULTS:

We identified a DNAm signature of 429 differentially methylated CpG sites in individuals with NCBRS. The genes to which these CpG sites map are involved in cell differentiation, calcium signaling, and neuronal function consistent with NCBRS pathophysiology. DNAm model classifications of VUS were concordant with the clinical phenotype; those within the SMARCA2 ATPase/helicase domain classified as "pathogenic". A patient with a mild neurodevelopmental NCBRS phenotype and a VUS distal to the ATPase/helicase domain did not score as pathogenic, clustering away from cases and controls. She demonstrated an intermediate DNAm profile consisting of one subset of signature CpGs with methylation levels characteristic of controls and another characteristic of NCBRS cases; each mapped to genes with ontologies consistent with the patient's unique clinical presentation.

CONCLUSIONS:

Here we find that a DNAm signature of SMARCA2 pathogenic variants in NCBRS maps to CpGs relevant to disorder pathophysiology, classifies VUS, and is sensitive to the position of the variant in SMARCA2. The patient with an intermediate model score demonstrating a unique genotype-epigenotype-phenotype correlation underscores the potential utility of this signature as a functionally relevant VUS classification system scalable beyond binary "benign" versus "pathogenic" scoring. This is a novel feature of DNAm signatures that could enable phenotypic predictions from genotype data. Our findings also demonstrate that DNAm signatures can be domain-specific, highlighting the precision with which they can reflect genotypic variation.

KEYWORDS:

BAF complex; Chromatin remodeling; DNA methylation; Epigenomics; NCBRS; SMARCA2; SWI/SNF; Signature; VUS

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