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Molecular genetic and clinical characterization of myotonic dystrophy type 1 patients carrying variant repeats within DMPK expansions

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Abstract

Myotonic dystrophy type 1 (DM1) is caused by a highly unstable expansion of CTG repeats in the DMPK gene. Its huge phenotypic variability cannot be explained solely by the repeat number. Recently, variant repeats within the DMPK expansions have emerged as potential disease modifiers. The frequency of variant expanded alleles was estimated in 242 DM1 patients from 174 Serbian families using repeat-primed PCR (RP-PCR). The patterns of variant repeats were determined by direct sequencing of RP-PCR or PCR products. PCR-based southern blot was performed to get insight into the intergenerational mutational dynamics of variant expanded alleles. All patients carrying variant repeats were clinically re-examined. Variant repeats were observed in eight patients from five families (2.9%). They were detected only at the 3′ end of DMPK expansions. CCG variant repeats were present in seven patients, either as a part of regular runs of CCGCTG hexamer, individual repeats, or CCG blocks. Analyses of three intergenerational transmissions revealed a considerable stability or likely a contraction of variant expanded alleles. Intriguingly, a decrease in age at onset accompanied these transmissions. Overall, patients were characterized by a milder phenotype and/or some atypical symptoms that could be rather clinically suggestive of myotonic dystrophy type 2. In addition, the first case of de novo CTC variant repeat was observed. Variant repeats might explain a part of the phenotypic variability in a small percent of DM1 patients and likely display a stabilizing effect on the meiotic instability of DMPK expanded alleles.

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Funding information

This study was supported by the Ministry of Education, Science and Technological Development, Republic of Serbia (grant nos. 173016 and 175083).

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Authors and Affiliations

  1. Faculty of Biology, Center for Human Molecular Genetics, University of Belgrade, Studentski trg 16, PO Box 43, Belgrade, 11000, Serbia

    Jovan Pešović, M. Brkušanin, G. Brajušković & Dušanka Savić-Pavićević

  2. Neurology Clinic, Clinical Center of Serbia, School of Medicine, University of Belgrade, Dr Subotica 6-8, Belgrade, 11000, Serbia

    S. Perić & V. Rakočević-Stojanović

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  1. Jovan Pešović
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  2. S. Perić
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  3. M. Brkušanin
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  6. Dušanka Savić-Pavićević
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Correspondence to Jovan Pešović or Dušanka Savić-Pavićević.

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The study was approved by the Ethical Committee of the University of Belgrade, School of Medicine. It was performed in accordance with the ethical standards of the 1964 Declaration of Helsinki and its later amendments.

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Pešović, J., Perić, S., Brkušanin, M. et al. Molecular genetic and clinical characterization of myotonic dystrophy type 1 patients carrying variant repeats within DMPK expansions. Neurogenetics 18, 207–218 (2017). https://doi.org/10.1007/s10048-017-0523-7

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  • DOI: https://doi.org/10.1007/s10048-017-0523-7

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