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Clin Epigenetics. 2019 Nov 4;11(1):156. doi: 10.1186/s13148-019-0749-3.

A genome-wide DNA methylation signature for SETD1B-related syndrome.

Author information

1
Amsterdam UMC, Department of Clinical Genetics, Genome Diagnostics laboratory Amsterdam, Reproduction & Development, University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands.
2
Amsterdam UMC, Department of Pediatrics, University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands.
3
Kennedy Krieger Institute, Department of Neurogenetics, 801 N. Broadway, Rm 564, Baltimore, MD, 21205, USA.
4
Department of Pathology and Laboratory Medicine, Western University, 800 Commissioner's Road E, London, ON, N6A 5W9, Canada.
5
University Medical Centre Groningen, University of Groningen, Department of Medical Genetics, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
6
Department of Pediatrics, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan.
7
National Epilepsy Centre, NHO, Shizuoka Institute of Epilepsy and Neurological Disorders, 886 Urushiyama, Aoi-ku, Shizuoka, 420-8688, Japan.
8
Department of medical genetics, CHU La Reunion-Groupe Hospitalier Sud Reunion, La Reunion, France.
9
Neurological Disorder Center Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Doha, Qatar.
10
Department of medical genetics, Hospices Civils de Lyon, Bron, France.
11
Department of Medical Genetics, Children's & Women's Health Centre of British Columbia University of British Columbia, C234-4500 Oak Street, Vancouver, British Columbia, V6H 3N1, Canada.
12
Biochemistry and Molecular Genetics Service, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Center for Biomedical Network Research on Rare Diseases (CIBERER), Barcelona, Spain.
13
Department of Human Genetics, Graduate School of Medicine, Yokohama City University, Fukuura 3-9, Kanazawa-ku, Yokohama, 236-0004, Japan.
14
Department of Genetics, Microbiology and Statistics, Faculty of Biology, University of Barcelona, av diagonal 643, 08028, Barcelona, Spain.
15
Department of Biochemistry, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan.
16
MassGeneral Hospital, Division of Medical Genetics and Metabolism, 175 Cambridge St, Suite 500, Boston, Massachusetts, 02114, USA.
17
Amsterdam UMC, Department of Clinical Genetics, Genome Diagnostics laboratory Amsterdam, Reproduction & Development, University of Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands. m.alders@amsterdamumc.nl.

Abstract

SETD1B is a component of a histone methyltransferase complex that specifically methylates Lys-4 of histone H3 (H3K4) and is responsible for the epigenetic control of chromatin structure and gene expression. De novo microdeletions encompassing this gene as well as de novo missense mutations were previously linked to syndromic intellectual disability (ID). Here, we identify a specific hypermethylation signature associated with loss of function mutations in the SETD1B gene which may be used as an epigenetic marker supporting the diagnosis of syndromic SETD1B-related diseases. We demonstrate the clinical utility of this unique epi-signature by reclassifying previously identified SETD1B VUS (variant of uncertain significance) in two patients.

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