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

Background: Myotonic dystrophy type 1 (DM1) is caused by expansion of an
unstable CTG repeat in the DMPK gene. The average number of repeats
reported in routine diagnostics is broadly correlated with disease
severity, but with limited predictive value and is not provided to
patients in genetic counselling. OPTIMISTIC is a large international
randomised trial of the efficacy of personalised cognitive behavioural
therapy and graded exercise in DM1. Objective: Evaluate the genetic basis
of symptomatic diversity in 250 adult, ambulant DM1 patients recruited
through OPTIMISTIC. 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 sex
and that patients with faster expansion rate develop symptoms earlier than
predicted. We quantified the critical role of variant repeats in delaying
age at onset by approximately 13.2 years (95% CI = 5.7 to 20.7, two-tailed
t-test, t = 3.7, p = 0.0019). Conclusions: Careful characterisation 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 the basis of
treatment response and stratification in DM1 trials. We suggest to
re-evaluate the recommended diagnostic criteria for DM1 and the potential
value of reporting more informative prognostic information to families.