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Am J Hum Genet. 2017 Mar 2;100(3):488-505. doi: 10.1016/j.ajhg.2017.01.033.

CpG Methylation, a Parent-of-Origin Effect for Maternal-Biased Transmission of Congenital Myotonic Dystrophy.

Author information

1
Department for Reproduction and Genetics, Vrije Universiteit Brussel, Brussels 1090, Belgium.
2
Genetics & Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
3
Centre for Medical Genetics, Universitair Ziekenhuis Brussel, Brussels 1090, Belgium.
4
The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, University of Toronto, Toronto, ON M5G 1E2, Canada.
5
Groupe de Recherche Interdisciplinaire sur les Maladies Neuromusculaires, Saguenay, QC 75204, Canada.
6
Genetics & Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; The Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
7
Genetics & Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; The Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Institute of Medical Science, School of Graduate Studies, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Pediatrics, University of Toronto, Toronto, ON M5S 1A1, Canada.
8
Department of Biology and Medical Genetics, Charles University Prague, Prague 128 00, Czech Republic.
9
The Prenatal Diagnosis and Medical Genetics Program, Department of Obstetrics and Gynecology, University of Toronto, Toronto, ON M5G 1E2, Canada; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
10
Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, University of Toronto, Toronto, ON M5G 1X5, Canada.
11
Department for Reproduction and Genetics, Vrije Universiteit Brussel, Brussels 1090, Belgium. Electronic address: karen.sermon@uzbrussel.be.
12
Genetics & Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; The Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: cepearson.sickkids@gmail.com.

Abstract

CTG repeat expansions in DMPK cause myotonic dystrophy (DM1) with a continuum of severity and ages of onset. Congenital DM1 (CDM1), the most severe form, presents distinct clinical features, large expansions, and almost exclusive maternal transmission. The correlation between CDM1 and expansion size is not absolute, suggesting contributions of other factors. We determined CpG methylation flanking the CTG repeat in 79 blood samples from 20 CDM1-affected individuals; 21, 27, and 11 individuals with DM1 but not CDM1 (henceforth non-CDM1) with maternal, paternal, and unknown inheritance; and collections of maternally and paternally derived chorionic villus samples (7 CVSs) and human embryonic stem cells (4 hESCs). All but two CDM1-affected individuals showed high levels of methylation upstream and downstream of the repeat, greater than non-CDM1 individuals (p = 7.04958 × 10-12). Most non-CDM1 individuals were devoid of methylation, where one in six showed downstream methylation. Only two non-CDM1 individuals showed upstream methylation, and these were maternally derived childhood onset, suggesting a continuum of methylation with age of onset. Only maternally derived hESCs and CVSs showed upstream methylation. In contrast, paternally derived samples (27 blood samples, 3 CVSs, and 2 hESCs) never showed upstream methylation. CTG tract length did not strictly correlate with CDM1 or methylation. Thus, methylation patterns flanking the CTG repeat are stronger indicators of CDM1 than repeat size. Spermatogonia with upstream methylation may not survive due to methylation-induced reduced expression of the adjacent SIX5, thereby protecting DM1-affected fathers from having CDM1-affected children. Thus, DMPK methylation may account for the maternal bias for CDM1 transmission, larger maternal CTG expansions, age of onset, and clinical continuum, and may serve as a diagnostic indicator.

KEYWORDS:

DMPK; DNA/CpG methylation; SIX5/DMAHP; congenital myotonic dystrophy; epigenetics; maternal transmission/maternal inheritance; myotonic dystrophy; parent-of-origin effect(s); pre-natal diagnosis; trinucleotide instability

PMID:
28257691
PMCID:
PMC5339342
DOI:
10.1016/j.ajhg.2017.01.033
[Indexed for MEDLINE]
Free PMC Article

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