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Lookup NU author(s): Dr Cecilia Jimenez MorenoORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
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.
Author(s): Cumming SA, Jimenez-Moreno C, Okkersen K, Wenninger S, Daidj F, Hogarth F, Littleford R, Gorman GS, Bassez G, Schoser B, Lochmuller H, van Engelen BGM, Monckton DG
Publication type: Article
Publication status: Published
Journal: Neurology
Year: 2019
Volume: 93
Issue: 10
Pages: e995-e1009
Print publication date: 03/09/2019
Online publication date: 08/08/2019
Acceptance date: 10/04/2019
Date deposited: 13/08/2019
ISSN (print): 0028-3878
ISSN (electronic): 1526-632X
Publisher: American Academy of Neurology
URL: https://doi.org/10.1212/WNL.0000000000008056
DOI: 10.1212/WNL.0000000000008056
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