Genetic Determinants of Disease Severity in the Myotonic Dystrophy Type 1 OPTIMISTIC Cohort

Overview

Journal Neurology

Specialty Neurology

Date 2019 Aug 10

PMID 31395669

Citations 39

Authors

Sarah A Cumming

Cecilia Jimenez-Moreno

Kees Okkersen

Stephan Wenninger

Ferroudja Daidj

Fiona Hogarth

Roberta Littleford

Grainne Gorman

Guillaume Bassez

Benedikt Schoser

Hanns Lochmuller

Baziel G M van Engelen

Darren G Monckton

Affiliations

Soon will be listed here.

Abstract

Objective: To evaluate the role of genetic variation at the 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 test = -3.7, = 0.0019).

Conclusions: Careful characterization of the 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.

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