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Abstract
Duchenne Muscular Dystrophy (DMD) is an X-linked neuromuscular disorder in which the detection of female carriers is of the utmost importance for genetic counseling. Haplotyping with polymorphic markers and quantitation of creatine kinase levels (CK) allow tracking of the at-risk haplotype and evidence muscle damage, respectively. Such approaches are useful for carrier detection in cases of unknown mutations. The lack of informative markers and the inaccuracy of CK affect carrier detection. Therefore, herein we designed novel mini-STR (Short Tandem Repeats) assays to amplify 10 loci within the DMD gene and estimated allele frequencies and the polymorphism information content among other parameters in 337 unrelated individuals from three Mexican populations. In addition, we tested the utility of the assays for carrier detection in three families. Moreover, given that serum levels of miR-206 discern between DMD patients and controls with a high area under the curve (AUC), the potential applicability for carrier detection was assessed. The serum levels of miR-206 of non-carriers (n = 24) and carriers (n = 23) were compared by relative quantitation using real-time PCR (p < 0.05), which resulted in an AUC = 0.80 in the Receiver Operating Characteristic curve analysis. In conclusion, miR-206 has potential as a “liquid biopsy” for carrier detection and genetic counseling in DMD.
Highlights
Pathogenic variants within the Duchenne Muscular Dystrophy (DMD) cause a spectrum of recognizable phenotypes known as dystrophinopathies
Most present-day Mexicans denominated “mestizos” as a population group, are the result of the ancestral admixture of different populations (Europeans, Amerindians and Africans). This process did not occur through all the geographical regions of Mexico; such heterogeneity in allele frequencies prevails nowadays [15]. This fact should be considered for genetic studies aimed at detecting candidate genes for medical traits as well as for applications of genetic variations such as the use of short tandem repeats (STRs) for the detection of the at-risk haplotypes in DMD [16]
Genetic diversity was analyzed based on allele frequencies of 10 STRs within the DMD in the three Mexican population samples (Table 1); for instance, 15 alleles were found for the 5 -5n4 marker (Figure 1C)
Summary
Pathogenic variants within the DMD cause a spectrum of recognizable phenotypes known as dystrophinopathies. Improvements in the integration of data derived from segregation analyses with informative DNA markers such as short tandem repeats (STRs) or single nucleotide polymorphisms (SNPs), the measurement of serum biomarkers such as CK and the consideration of familiar structure allow reliable calculation of recurrence risks with specialized software such as RiscalW [8]. Limitations of such approaches are: (1) Low heterozygosity affects segregation analysis, since the detection of different alleles between affected and unaffected males allows the indirect detection of the at-risk haplotype.
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