Abstract
Genotype-to-phenotype correlation studies in myotonic dystrophy type 1 (DM1) have been confounded by the age-dependent, tissue-specific and expansion-biased features of somatic mosaicism of the expanded CTG repeat. Previously, we showed that by controlling for the confounding effects of somatic instability to estimate the progenitor allele CTG length in blood DNA, age at onset correlations could be significantly improved. To determine the suitability of saliva DNA as a source for genotyping, we used small pool-PCR to perform a detailed quantitative study of the somatic mutational dynamics of the CTG repeat in saliva and blood DNA from 40 DM1 patients. Notably, the modal allele length in saliva was only moderately higher in saliva and not as large as previously observed in most other tissues. The lower boundary of the allele distribution was also slightly higher in saliva than it was in blood DNA. However, the progenitor allele length estimated in blood explained more of the variation in age at onset than that estimated from saliva. Interestingly, although the modal allele length was slightly higher in saliva, the overall degree of somatic variation was typically lower than in blood DNA, revealing new insights into the tissue-specific dynamics of somatic mosaicism. These data indicate that saliva constitutes an accessible, non-invasive and suitable DNA sample source for performing genetic studies in DM1.
Highlights
Myotonic dystrophy type 1 (DM1) is the most common dominantly inherited myopathy in adults
They described some features that we found in our larger cohort: the progenitor allele length was higher and the levels of somatic instability were lower in buccal cells than in blood, with some differences in the CTCF binding sites flanking the (CTG) mutational dynamics between both tissues, but with overall much more slower dynamics, triggered by the presence of variant repeats that confers stability to the CTG repeat tract [27, 33]
By comparing two tissue sources, our study has assessed the suitability of employing buccal cells as an alternative tissue source of genetic material to carry out informative molecular analyses in DM1, providing more accurate prognostic information, something that cannot be done with other DM1 tissues due to the excessively large repeat size compared to blood and buccal cells from saliva
Summary
Peripheral blood and saliva samples were collected simultaneously from 40 Costa Rican DM1 patients (21 women and 19 men): three late-onset cases, 31 classic adult-onset cases, three juvenile-onset cases, two congenital-onset cases and one carrier subject who was asymptomatic at sampling. The DM1 population has already been well characterized and the age of onset has been previously recorded and reported [16, 18]. Age of onset was recorded after clinical evaluation by one of four different experienced neurologists, or after an interview by the same neurologists or by one of two different experienced clinical geneticists. The Scientific-Ethics Committee of the Universidad de Costa Rica approved the project.
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