Abstract
Myotonic dystrophy type 1 (DM1) is caused by the expansion of an unstable CTG repeat (g.17294_17296(45_1000)) with more repeats associated with increased disease severity and reduced age at onset. Expanded disease-associated alleles are highly unstable in both the germline and soma. Germline instability is expansion biased, providing a molecular explanation for anticipation. Somatic instability is expansion biased, size- and age-dependent, features that have compromised genotype–phenotype correlations and intergenerational studies. We corrected these confounding factors by estimating the progenitor allele length in 54 father–offspring and 52 mother–offspring pairs in Costa Rican DM1 families. Not surprisingly, we found major parental allele length effects on the size of the allele transmitted, the magnitude of the intergenerational length change, the age at onset in the next generation and the degree of anticipation in both male and female transmissions. We also detected, for the first time, an age-of-parent effect for both male and female transmission. Interestingly, we found no evidence for an intrauterine effect in the transmission of congenital DM1, suggesting previous reports may have been an artefact of age-dependent somatic instability and sampling bias. These data provide new insights into the germline dynamics of the CTG repeat and opportunities for providing additional advice and more accurate risk assessments to prospective parents in DM1 families.
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Acknowledgements
We thank our colleagues in the DGM group for productive discussions and helpful comments on the manuscript. We also thank the myotonic dystrophy patients and their families for their assistance. This work was supported by awards from: the Muscular Dystrophy Association; the Universidad de Costa Rica; the Ministerio de Ciencia y Tecnologia of Costa Rica; and the National Council for Scientific and Technological Research in Costa Rica (CONICIT).
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Morales, F., Vásquez, M., Cuenca, P. et al. Parental age effects, but no evidence for an intrauterine effect in the transmission of myotonic dystrophy type 1. Eur J Hum Genet 23, 646–653 (2015). https://doi.org/10.1038/ejhg.2014.138
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DOI: https://doi.org/10.1038/ejhg.2014.138
