De novo repeat interruptions are associated with reduced somatic instability and mild or absent clinical features in myotonic dystrophy type 1

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Myotonic dystrophy type 1 (DM1) is a multisystem disorder, caused by expansion of a CTG trinucleotide repeat in the 3′-untranslated region of the DMPK gene. The repeat expansion is somatically unstable and tends to increase in length with time, contributing to disease progression. In some individuals, the repeat array is interrupted by variant repeats such as CCG and CGG, stabilising the expansion and often leading to milder symptoms. We have characterised three families, each including one person with variant repeats that had arisen de novo on paternal transmission of the repeat expansion. Two individuals were identified for screening due to an unusual result in the laboratory diagnostic test, and the third due to exceptionally mild symptoms. The presence of variant repeats in all three expanded alleles was confirmed by restriction digestion of small pool PCR products, and allele structures were determined by PacBio sequencing. Each was different, but all contained CCG repeats close to the 3′-end of the repeat expansion. All other family members had inherited pure CTG repeats. The variant repeat-containing alleles were more stable in the blood than pure alleles of similar length, which may in part account for the mild symptoms observed in all three individuals. This emphasises the importance of somatic instability as a disease mechanism in DM1. Further, since patients with variant repeats may have unusually mild symptoms, identification of these individuals has important implications for genetic counselling and for patient stratification in DM1 clinical trials.

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We thank all participants in the DMGV study for their co-operation, in particular the members of the three families described here. Electromyography in patient DMGV182 was undertaken by Dr. Gregory Moran, Department of Clinical Neurophysiology, Western General Hospital, Edinburgh. Acknowledgement of grant support: Muscular Dystrophy Association (252524); Wellcome Trust Institutional Strategic Support Fund (ISSF) (097821/Z/11/Z); Muscular Dystrophy UK (formerly Muscular Dystrophy Campaign) (MC3/1073); Chief Scientist Office (CAF/MD/15/01).

The Scottish Myotonic Dystrophy Consortium

Cheryl Longman, Douglas Wilcox, Alison Wilcox, Richard Petty, Yvonne Robb, Maria Elena Farrugia, Helen Gregory, Alexis Duncan, Catherine McWilliam, John Dean, Anne-Marie Taylor, Lorna MacLeish, Monika Rahman, Anne McKeown, Kirsten Patterson, Mark Hamilton, Bob Ballantyne, Sarah Cumming and Darren G Monckton.

The Scottish Myotonic Dystrophy Consortium is a subgroup of the Scottish Muscle Network; Programme Manager Hugh Kennedy, Programme Support Officer Laura Craig.

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Correspondence to Mark J. Hamilton.

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Conflict of interest

Professor Monckton has been a paid scientific consultant of Biogen Idec, AMO Pharma, Charles River and Vertex Pharmaceuticals. Professor Monckton also has a research contract with AMO Pharma.

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