Dataset Information

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

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.

SUBMITTER: Barbe L

PROVIDER: S-EPMC5339342 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Barbé Lise L Lanni Stella S López-Castel Arturo A Franck Silvie S Spits Claudia C Keymolen Kathelijn K Seneca Sara S Tomé Stephanie S Miron Ioana I Letourneau Julie J Liang Minggao M Choufani Sanaa S Weksberg Rosanna R Wilson Michael D MD Sedlacek Zdenek Z Gagnon Cynthia C Musova Zuzana Z Chitayat David D Shannon Patrick P Mathieu Jean J Sermon Karen K Pearson Christopher E CE

American journal of human genetics 20170301 3

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 wit ...[more]

PMID: 28257691

Similar Datasets

Project description:Abstract BACKGROUND: Congenital Myotonic Dystrophy (CDM) is the harshest form of Myotonic Dystrophy type 1 (DM1,OMIM #160900). The mode of inheritance is autosomal dominant, and results from a microsatellite expansion in DMPK with an incidence of 2.1:1000,000 live births in Canada. The principal clinical signs during the neonatal period are myopathic facies, hypotonia and weakness resulting in such features as talipes equinovarus, nutritional, cardiac and respiratory problems. OBJECTIVES: To describe the main findings of CDM in the perinatal period. DESIGN/METHODS: A five year prospective cohort study from 2005 to 2010 of eligible incident cases of CDM was performed via the Canadian Pediatric Surveillance Program (CPSP). Reporting physicians completed a questionnaire with the medical history at birth and during the perinatal period. Our patients met the CDM criteria proposed by Campbell et al. (2013): 1) CDM symptoms with hospitalization greater of 72 hours; and 2) CTGrs above 200. RESULTS: We obtained 43 questionnaires, 22 female and 21 male (F:M ratio of 1.04:1). Average CTG repeat size (CGTrs) was 795.67 (250-2300). The main complication during the prenatal period was polyhydramnios (n=20). The majority of the patients (n=27) had full term pregnancy and with normal birth weight (n=25). Average Apgar was 4 at 1 (range 1-9), and 6 for 5 and 10. Intubation was required in 29/43 of the cases, with an average hospital stay of 43.5 days. Nutritional support (ie ng feeds) was required in 34/43, and it was longer than 14 days in 21 patients. Nine patients died, 6 of them due to respiratory failure. Four deaths were withdrawal of life support. CONCLUSION: The respiratory difficulties are well described as the principal complication in CDM (Ho et al. [2015]), but we found that the necessity of multiple nutritional interventions was the most frequent neonatal complication (79%), respiratory complications remains as the principal cause of death (66.6%). Zaki et al. (2010) describes a cohort with a 100% frequency of polyhydramnios, differing on ours where it is 46.5%. We conclude that CDM is not always evident prenatally by polyhydramnios, IUGR or preterm delivery. Nutritional and respiratory assessments should be prioritized, and nutritional interventions may extend for long periods of time. Despite high respiratory and feeding support needs, the majority of patients improved over time. Hence the importance of prenatal counseling and preparation for the complications in the neonatal period.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets