Genetic determinants of disease severity in the myotonic dystrophy type 1 OPTIMISTIC cohort

Cumming, S. A. et al. (2019) Genetic determinants of disease severity in the myotonic dystrophy type 1 OPTIMISTIC cohort. Neurology, 93(10), e995-e1009. (doi: 10.1212/WNL.0000000000008056) (PMID:31395669) (PMCID:PMC6745735)

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Objective: To evaluate the role of genetic variation at the DMPK locus on symptomatic diversity in 250 adult, ambulant patients with myotonic dystrophy type 1 (DM1) recruited to the Observational Prolonged Trial in Myotonic Dystrophy Type 1 to Improve Quality of Life—Standards, a Target Identification Collaboration (OPTIMISTIC) clinical trial. Methods: We used small pool PCR to correct age at sampling biases and estimate the progenitor allele CTG repeat length and somatic mutational dynamics, and AciI digests and repeat primed PCR to test for the presence of variant repeats. Results: We confirmed disease severity is driven by progenitor allele length, is further modified by age, and, in some cases, sex, and that patients in whom the CTG repeat expands more rapidly in the soma develop symptoms earlier than predicted. We revealed a key role for variant repeats in reducing disease severity and quantified their role in delaying age at onset by approximately 13.2 years (95% confidence interval 5.7–20.7, 2-tailed t test t = −3.7, p = 0.0019). Conclusions: Careful characterization of the DMPK CTG repeat to define progenitor allele length and presence of variant repeats has increased utility in understanding clinical variability in a trial cohort and provides a genetic route for defining disease-specific outcome measures, and the basis of treatment response and stratification in DM1 trials.

Item Type:Articles
Additional Information:Study funded by European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement number 305697 (the OPTIMISTIC project) and donations to the DGM group from the Myotonic Dystrophy Support Group.
Glasgow Author(s) Enlighten ID:Cumming, Dr Sarah and Monckton, Professor Darren
Authors: Cumming, S. A., Jimenez-Moreno, C., Okkersen, K., Wenninger, S., Daidj, F., Hogarth, F., Littleford, R., Gorman, G., Bassez, G., Schoser, B., Lochmüller, H., van Engelen, B. G.M., and Monckton, D. G.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:Neurology
Publisher:American Academy of Neurology
ISSN (Online):1526-632X
Published Online:08 August 2019
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in Neurology 93(10):e995-e1009
Publisher Policy:Reproduced under a Creative Commons license

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