Frequency and stability of the myotonic dystrophy type 1 premutation

Background: Myotonic dystrophy type 1 (DM1) is associated with the expansio n of an unstable CTG repeat. Larger alleles are associated with a more seve re form of the disease and almost always increase in length from one genera tion to the next, accounting for the clinical anticipation characteristic o f DM1. As such, expanded alleles are rapidly lost from the population. Howe ver, the incidence of the disease appears to remain constant. It was the au thors' our aim to determine the frequency and germline stability of the DM1 premutation alleles that give rise to new DM1 families. Methods: The autho rs measured the size of the DM1 CTG repeat in blood DNA derived from a larg e number of individuals in DM1 families, including distant and unaffected r elatives. Results: It was determined that DM1 premutation alleles can be id entified both in distant relatives of DM1 probands and more rarely in unaff ected spouses. These premutation alleles are not directly associated with a clinical phenotype in the carrier but are highly unstable and liable to ex pand in succeeding generations, particularly when transmitted by a man. In addition, the authors observed occasional expansion-biased instability of a lleles within the high end of the normal size range. Conclusions: Individua ls carrying premutation alleles are at high risk of having affected offspri ng within a limited number of generations. Such data indicate that premutat ion alleles cannot be the long-term source of new DM1 families, which must ultimately arise from mutations of alleles within the upper normal size ran ge.