Allele length of the DMPK CTG repeat is a predictor of progressive myotonic dystrophy type 1 phenotypes

Abstract

Myotonic dystrophy type 1 (DM1) is an autosomal dominant inherited disorder, caused by expansion of a germline and somatically unstable CTG repeat in the DMPK gene. Previously, CTG repeat length at birth has been correlated to patient age at symptom onset. Attempts to correlate CTG repeat length with progressive DM1 phenotypes, such as muscle power, have proven difficult. To better correlate genotype with progressive phenotypes, we have measured CTG repeat tract length and screened for interrupting variant repeats in 192 study participants from a well-characterized Canadian cohort. We have assessed genotype-phenotype correlations with nine progressive measures of skeletal muscle power and respiratory function. We have built statistical models which include confounding factors such as sex, age, height and weight to further explain variation in muscle power. Our analysis reveals a strong correlation between DM1 genotype and respiratory function and skeletal muscle power, as part of a complex model which includes additional modulators such as sex, age, height, weight, and the presence or absence of interrupting variant repeats. Distal skeletal muscle measurements, such as hand pinch and grip strength, show the strongest correlation with disease genotype. Detailed analysis of CTG repeat length, and incorporation of confounding factors, greatly improves the predictive ability of these models. They reveal a greater genetic influence on individual progressive phenotypes than on age at symptom onset, and for clinical trials will help optimise stratification and explain patient variability. They will also help practitioners prioritise assessment of the muscular power measurements which correlate best with disease severity.

Activities of daily living in myotonic dystrophy type 1

“…These have previously been shown to result in reduced somatic instability and delayed disease onset . Further, in several different phenotypic measures, individuals with variant repeats scored better . This does not appear to be the case in the current study for the DM1‐Activ C total score, which did not differ significantly between individuals with and without variant repeats.…”

“…Five patients in the PhenoDM1 cohort were found to have AciI‐sensitive variant repeat interruptions. These have previously been shown to result in reduced somatic instability and delayed disease onset . Further, in several different phenotypic measures, individuals with variant repeats scored better .…”

“…17,18 Further, in several different phenotypic measures, individuals with variant repeats scored better. 17,18 This does not appear to be the case in the current study for the DM1-Activ C total score, which did not differ significantly between individuals with and without variant repeats. However, the number of identified individuals bearing variant repeats in the cohort is relatively small.…”

Towards development of a statistical framework to evaluate myotonic dystrophy type 1 mRNA biomarkers in the context of a clinical trial

“…In this context, and taking into account the modest size of this study, the most significant correlation, i.e. between effective CTG length as predicted from DM1-APA and the true CTG length as measured using PCR (R 2 =0.29) actually compares favourably with symptoms most strongly correlated in similar studies, such as correlation of CTG repeat length and grip strength (R 2 =0.443), pinch strength (R 2 =0.419) and ankle dorsiflexor strength (R 2 =0.202) [19].…”

“…It is well established that the primary determinant of both age at onset and many progressive DM1 symptoms is the CTG repeat length [18][19][20]. Separate efforts have shown that case/control status in DM1 results in detectable AS changes in the mRNA profile of skeletal muscle (Nakamori et al 2013;Batra et al 2014).…”