Toggle Main Menu Toggle Search

Open Access padlockePrints

Genetic Determinants of disease severity in the myotonic dystrophy type 1 OPTIMISTIC Cohort

Lookup NU author(s): Dr Cecilia Jimenez Moreno



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.

Publication metadata

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


DOI: 10.1212/WNL.0000000000008056


Altmetrics provided by Altmetric


Find at Newcastle University icon    Link to this publication