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

, Sarah A. Cumming, Cecilia Jimenez-Moreno, Kees Okkersen, Stephan Wenninger, Ferroudja Daidj, Fiona Hogarth, Roberta Littleford, Gráinne Gorman, Guillaume Bassez, Benedikt Schoser, Hanns Lochmüller, Baziel G. M. van Engelen, Darren G. Monckton (Lead / Corresponding author)

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Abstract

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.

Original languageEnglish
Pages (from-to)e995-e1009
Number of pages16
JournalNeurology
Volume93
Issue number10
Early online date8 Aug 2019
DOIs
Publication statusPublished - 3 Sep 2019

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    , 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., & Monckton, D. G. (2019). Genetic determinants of disease severity in the myotonic dystrophy type 1 OPTIMISTIC cohort. Neurology, 93(10), e995-e1009. https://doi.org/10.1212/WNL.0000000000008056