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

Cumming, S. A. et al. (2018) De novo repeat interruptions are associated with reduced somatic instability and mild or absent clinical features in myotonic dystrophy type 1. European Journal of Human Genetics, 26(11), pp. 1635-1647. (doi:10.1038/s41431-018-0156-9) (PMID:29967337) (PMCID:PMC6189127)

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Abstract

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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Hamilton, Dr Graham and Cooper, Dr Anneli and Adam, Mrs Berit and Cumming, Dr Sarah and Hamilton, Mark and Monckton, Professor Darren and McGhie, Mrs Josephine and Herzyk, Dr Pawel
Authors: Cumming, S. A., Hamilton, M. J., Robb, Y., Gregory, H., McWilliam, C., Cooper, A., Adam, B., McGhie, J., Hamilton, G., Herzyk, P., Tschannen, M. R., Worthey, E., Petty, R., Ballantyne, B., The Scottish Myotonic Dystrophy Consortium, , Warner, J., Farrugia, M. E., Longman, C., and Monckton, D. G.
College/School:College of Medical Veterinary and Life Sciences > Institute of Biodiversity Animal Health and Comparative Medicine
College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:European Journal of Human Genetics
Publisher:Nature Publishing Group
ISSN:1018-4813
ISSN (Online):1476-5438
Published Online:02 July 2018
Copyright Holders:Copyright © 2018 European Society of Human Genetics
First Published:First published in European Journal of Human Genetics 26(11)L 1635-1647
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
742591Institutional Strategic Support Fund (2016)Anna DominiczakWellcome Trust (WELLCOTR)204820/Z/16/ZRI CARDIOVASCULAR & MEDICAL SCIENCES
617601Next generation sequencing (NGS) approaches to genotyping in myotonic dystrophy type 1 (ISSF Catalyst Fund)Darren MoncktonWellcome Trust (WELLCOTR)097821/Z/11/ZRI MOLECULAR CELL & SYSTEMS BIOLOGY
663161Structural CNS changes, neuropsychological impairment and sleep disturbance in type 1 Myotonic dystrophy - a genotype-phenotype studyDarren MoncktonMuscular Dystrophy UK (MUSCDYST)MC3/1073/1RI MOLECULAR CELL & SYSTEMS BIOLOGY