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Am J Hum Genet. 2017 May 4;100(5):773-788. doi: 10.1016/j.ajhg.2017.04.004.

CHARGE and Kabuki Syndromes: Gene-Specific DNA Methylation Signatures Identify Epigenetic Mechanisms Linking These Clinically Overlapping Conditions.

Author information

1
Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
2
Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, M5S 1A1, Canada.
3
Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada; Centre for Computational Medicine, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
4
Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada; Department of Pediatrics, University of Toronto, Toronto, Ontario, M5S 1A1, Canada.
5
Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada; Department of Pediatrics, University of Toronto, Toronto, Ontario, M5S 1A1, Canada.
6
Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, M5S 1A1, Canada; Department of Pediatrics, University of Toronto, Toronto, Ontario, M5S 1A1, Canada; Prenatal Diagnosis and Medical Genetics Program, Mount Sinai Hospital, Toronto, Ontario, M5G 1X5, Canada.
7
Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario M5G 1X8 Canada.
8
PreventionGenetics, Marshfield, WI, 54449, USA.
9
Department of Medical Genetics, University of Alberta, Edmonton, Alberta, T6G 2R3, Canada.
10
Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
11
Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, L8S 4L8, Canada.
12
National Centre for Medical Genetics, Our Lady's Children's Hospital, Crumlin, Dublin 12, Ireland.
13
Service de Génétique, Centre de Référence Anomalies du Développement de l'Ouest, CHU Poitiers, 86021 Poitiers, France; EA3808, Université de Poitiers, France.
14
Département de Génétique, APHP-Hôpital Robert DEBRE, 75019 Paris, France.
15
Center for Human Genetics Inc., Cambridge, MA 02139, USA.
16
Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario M5G 1X8 Canada; Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, M5S 1A1, Canada.
17
Otolaryngology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada; Department of Otolaryngology, University of Toronto, Toronto, Ontario, M5S 1A1, Canada; Institute of Medical Sciences, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
18
Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, M5S 1A1, Canada; Genome Diagnostics, Department of Clinical Laboratory Genetics, University Health Network, Canada.
19
Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, M5S 1A1, Canada; The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario M5G 1X8 Canada; McLaughlin Centre, University of Toronto, Toronto, Ontario, M5S 1A1, Canada.
20
Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada; Centre for Computational Medicine, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada; Department of Computer Science, University of Toronto, Toronto, Ontario, M5S 1A1, Canada.
21
Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, M5S 1A1, Canada; Department of Pediatrics, University of Toronto, Toronto, Ontario, M5S 1A1, Canada; Institute of Medical Sciences, University of Toronto, Toronto, Ontario M5S 1A8, Canada. Electronic address: rweksb@sickkids.ca.

Abstract

Epigenetic dysregulation has emerged as a recurring mechanism in the etiology of neurodevelopmental disorders. Two such disorders, CHARGE and Kabuki syndromes, result from loss of function mutations in chromodomain helicase DNA-binding protein 7 (CHD7LOF) and lysine (K) methyltransferase 2D (KMT2DLOF), respectively. Although these two syndromes are clinically distinct, there is significant phenotypic overlap. We therefore expected that epigenetically driven developmental pathways regulated by CHD7 and KMT2D would overlap and that DNA methylation (DNAm) alterations downstream of the mutations in these genes would identify common target genes, elucidating a mechanistic link between these two conditions, as well as specific target genes for each disorder. Genome-wide DNAm profiles in individuals with CHARGE and Kabuki syndromes with CHD7LOF or KMT2DLOF identified distinct sets of DNAm differences in each of the disorders, which were used to generate two unique, highly specific and sensitive DNAm signatures. These DNAm signatures were able to differentiate pathogenic mutations in these two genes from controls and from each other. Analysis of the DNAm targets in each gene-specific signature identified both common gene targets, including homeobox A5 (HOXA5), which could account for some of the clinical overlap in CHARGE and Kabuki syndromes, as well as distinct gene targets. Our findings demonstrate how characterization of the epigenome can contribute to our understanding of disease pathophysiology for epigenetic disorders, paving the way for explorations of novel therapeutics.

KEYWORDS:

CHARGE syndrome; DNA methylation; Epigenetics; Kabuki syndrome; chromodomain helicase DNA-binding protein 7 (CHD7); lysine (K) methyltransferase 2D (KMT2D)

PMID:
28475860
PMCID:
PMC5420353
DOI:
10.1016/j.ajhg.2017.04.004
[Indexed for MEDLINE]
Free PMC Article

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