Diagnostic problems in congenital myotonic dystrophy

DiRocco, M.; Gennarelli, Massimo; Veneselli, Edvige; Bado, M.; Romanengo, Marta; Celle, M. E.; Cordone, G; Borrone, C

doi:10.1007/bf02282900

Cited by 3 publications

(2 citation statements)

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“…Prenatal diagnosis of CDM1 is hampered by the poor association of repeat size to clinical presentation. 4,5,[23][24][25][27][28][29]43,109 Remarkably, for each of the three CVSs with paternally derived CTG expansions, methylation was present only downstream of the repeat, while for all four maternally transmitted CVSs, methylation was present both upstream and downstream of the repeat (Tables 1 and S1, Figure 3). This strong methylation pattern was also observed in the four hESC lines studied, with methylation upstream in all the maternally inherited lines, and no difference in methylation, based on inheritance, downstream of the CTG repeat (Tables 1 and S1, Figure 3).…”

Section: Discussionmentioning

confidence: 99%

“… 10 , 20 , 21 , 22 , 23 , 24 , 25 , 26 Moreover, prenatal tissues (amniocentesis or chorionic villus sampling) from pregnancies that led to the birth of CDM1-affected children can have repeat lengths considerably shorter than 1,000 repeats, even fewer than the transmitting mother—complicating a definite prenatal diagnosis based only upon repeat length. 18 , 24 , 26 , 27 , 28 , 29 , 30 Similarly, some individuals with CTG expansions >1,000 repeats present with very mild symptoms with late onset, one case as late as 44 years old. 18 , 19 , 20 Ongoing somatic CTG repeat expansions can hamper correlations of repeat length to disease state.…”

Section: Introductionmentioning

confidence: 99%

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

Barbé

Lanni

López-Castel

et al. 2017

The American Journal of Human Genetics

128

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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). 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.

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