Known Value of CTG Repeat Length as a Biomarker
The identification and validation of a prognostic biomarker can have considerable value for DM1 stakeholders, from improving the ability to provide informed patient care to stratifying subjects in an interventional clinical trial. Theoretically, CTG progenitor allele length at birth should provide such value because of the relationship between repeat length, somatic instability, MBNL sequestration, and mis-splicing and, in turn, determining DM1 symptomatology. Yet, to date, expanded CTG repeat length has been strongly correlated only with patient age at symptom onset. Its value as a predictive biomarker lies in the establishment of stronger ties to measures of disease progression and, subsequently, to the efficacy of a candidate therapeutic. Due to the heterogeneity of DM1, achieving this goal requires detailed genotypic and phenotypic characterization of well-powered cohorts.
Controlling for Confounders Improves Predictive Value
The presence of variants in expanded CTG tracts in DMPK is associated with delayed age of DM1 onset, supporting the need to distinguish pure CTG from interrupted expansions (Braida et al., 2010). Drs. Darren Monckton (University of Glasgow), Cynthia Gagnon (Université de Sherbrooke), and colleagues sought to determine whether taking into account interrupting variant repeats in CTG expansions and other potential confounding factors could improve the predictive value of CTG repeat length for a broader array of patient phenotypic traits (Overend et al., 2019).
Using phenotypic data from 192 subjects in the Saguenay-Lac-Saint-Jean population of DM1 patients, the research team determined progenitor CTG expanded allele length, determined presence/absence of interrupted repeats, and looked for correlations with a range of objective measures of respiratory function and skeletal muscle power. Nine percent of subjects were found to exhibit interrupted repeat tracts (with runs of CCG or CGG).
Correlations of age at onset (available for 77% of the cohort) confirmed that progenitor expanded CTG length was a key modifier of age at DM1 symptom onset. The presence of variant repeat tracts was associated with later age of symptom onset. Somatic instability (difference between progenitor allele length and length at time of evaluation for this study) showed that instability was strongly correlated with progenitor allele length and whether the repeat tract included non-CTG interruptions. Measures of respiratory and skeletal muscle function were strongly correlated with progenitor allele length. Finally, the presence/absence of interrupted CTG tracts in DMPK was the most important factor in all measures of skeletal muscle function.
Taken together, the presence of interruptions among DMPK CTG expansions significantly decreased somatic instability and, in turn, increased the age of symptom onset. Moreover, these patients were less severely affected than would be expected given their CTG expansion length. The research team notes that it is likely that these patients also show slower progression, although that remains to be confirmed in longitudinal studies.
Finally, taking the presence/absence of repeat interruptions into account, modal CTG length may prove to be an improved predictor of time of onset and rate of progression of DM1. Thus, complete genotype assessments are essential in establishing prognosis and patient management plans, as well as important stratification factors for interventional clinical trials. The team concludes that outcome measures that correlate best with genotype are potentially the best decision-making measures for interventional clinical trials in DM1.
Variant CCG and GGC repeats within the CTG expansion dramatically modify mutational dynamics and likely contribute toward unusual symptoms in some myotonic dystrophy type 1 patients.
Braida C, Stefanatos RK, Adam B, Mahajan N, Smeets HJ, Niel F, Goizet C, Arveiler B, Koenig M, Lagier-Tourenne C, Mandel JL, Faber CG, de Die-Smulders CE, Spaans F, Monckton DG.
Hum Mol Genet. 2010 Apr 15;19(8):1399-412. doi: 10.1093/hmg/ddq015. Epub 2010 Jan 15
Allele length of the DMPK CTG repeat is a predictor of progressive myotonic dystrophy type 1 phenotypes.
Overend G, Légaré C, Mathieu J, Bouchard L, Gagnon C, Monckton DG.
Hum Mol Genet. 2019 Jul 1;28(13):2245-2254. doi: 10.1093/hmg/ddz055.