TY - JOUR
T1 - Genetic determinants of disease severity in the myotonic dystrophy type 1 OPTIMISTIC cohort
AU - OPTIMISTIC consortium
AU - Cumming, Sarah A.
AU - Jimenez-Moreno, Cecilia
AU - Okkersen, Kees
AU - Wenninger, Stephan
AU - Daidj, Ferroudja
AU - Hogarth, Fiona
AU - Littleford, Roberta
AU - Gorman, Gráinne
AU - Bassez, Guillaume
AU - Schoser, Benedikt
AU - Lochmüller, Hanns
AU - van Engelen, Baziel G. M.
AU - Monckton, Darren G.
N1 - Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
PY - 2019/9/3
Y1 - 2019/9/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85071786473&partnerID=8YFLogxK
U2 - 10.1212/WNL.0000000000008056
DO - 10.1212/WNL.0000000000008056
M3 - Article
C2 - 31395669
SN - 0028-3878
VL - 93
SP - e995-e1009
JO - Neurology
JF - Neurology
IS - 10
ER -