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Replacement of the myotonic dystrophy type 1 CTG repeat with ‘non-CTG repeat’ insertions in specific tissues
  1. Michelle M Axford1,2,
  2. Arturo López-Castel1,3,
  3. Masayuki Nakamori4,
  4. Charles A Thornton4,
  5. Christopher E Pearson1,2
  1. 1Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada
  2. 2Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
  3. 3Valentia Biopharma, Parque Científico de la Universidad de Valencia, Paterna, Spain
  4. 4Department of Neurology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
  1. Correspondence to Dr Christopher E Pearson, Genetics and Genome Biology, The Hospital for Sick Children, TMDT Building 101 College Street, 15th Floor, Rm 15-312 East Tower, Toronto, ON M5G 1L7, Canada; cepearson.sickkids{at}


Background Recently, curious mutations have been reported to occur within the (CTG)n repeat tract of the myotonic dystrophy type 1 (DM1) locus. For example, the repeat, long presumed to be a pure repeat sequence, has now been revealed to often contain interruption motifs in a proportion of cases with expansions. Similarly, a few de novo somatic CTG expansions have been reported to arise from non-expanded DM1 alleles with 5–37 units, thought to be genetically stable.

Aims and methods This study has characterised a novel mutation configuration at the DM1 CTG repeat that arose as somatic mosaicism in a juvenile onset DM1 patient with a non-expanded allele of (CTG)12 and tissue specific expansions ranging from (CTG)1100 to 6000.

Results The mutation configuration replaced the CTG tract with a non-CTG repeat insertion of 43 or 60 nucleotides, precisely placed in the position of the CTG tract with proper flanking sequences. The inserts appeared to arise from a longer human sequence on chromosome 4q12, and may have arisen through DNA structure mediated somatic inter-gene recombination or replication/repair template switching errors. De novo insertions were detected in cerebral cortex and skeletal muscle, but not in heart or liver. Repeat tracts with −1 or −2 CTG units were also detected in cerebellum, which may have arisen by contractions of the short (CTG)12 allele.

Conclusion This non-CTG configuration expands current understanding of the sequence variations that can arise at this hypermutable site.

  • Myotonic dystrophy
  • non-CTG repeat
  • de novo mutation
  • insertions trinucleotide repeats
  • genetics
  • clinical genetics
  • molecular genetics
  • muscle disease
  • neuromuscular disease

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  • MMA and ALC contributed equally.

  • Funding This work was supported by the Canadian Institutes of Health Research (CIHR) (CEP), the Muscular Dystrophy Canada (CEP), by the University of Rochester Paul Wellstone Muscular Dystrophy Cooperative Research Center with support from the NIH (grant U54NS48843) (CEP and CAT), The Muscular Dystrophy Association USA (MDAUSA) (CAT), a Doctoral Training Award from the CIHR Collaborative Graduate Training Program in Molecular Medicine (MMA), and an Ontario Graduate Scholarship (MMA), a postdoctoral fellowship from The Hospital for Sick Children Research Training Centre (ALC), and a postdoctoral fellowships from the MDAUSA and the Cell Science Research Foundation and the Uehara Memorial Foundation (MN). Mutant sequences were deposited to GenBank (accession numbers JF697199, JF697200and JF697201).

  • Competing interests None.

  • Ethics approval This study was conducted with the approval of the University of Rochester.

  • Provenance and peer review Not commissioned; externally peer reviewed.