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Frequency and stability of the myotonic dystrophy type 1 premutation

Servei de Genètica (Drs. Martorell and Baiget), Hospital de Sant Pau, Barcelona, Spain; Division of Molecular Genetics (Dr. Monckton), Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow, UK; Servei de Genètica (Dr. Sanchez), Hospital Clinic, Barcelona, Spain; Servicio de Neurología (Dr. Munain), Hospital Ntra. Sra. De Aranzazu, San Sebastián, Guipuzcoa, Spain.

Address correspondence and reprint requests to Dr. Loreto Martorell, Servei de Genètica, Hospital de Sant Pau, Pare Claret 167, 08025-Barcelona, Spain; e-mail: mmartorells{at}hsp.santpau.es

BACKGROUND: Myotonic dystrophy type 1 (DM1) is associated with the expansion of an unstable CTG repeat. Larger alleles are associated with a more severe form of the disease and almost always increase in length from one generation to the next, accounting for the clinical anticipation characteristic of DM1. As such, expanded alleles are rapidly lost from the population. However, the incidence of the disease appears to remain constant. It was the authors’ our aim to determine the frequency and germline stability of the DM1 premutation alleles that give rise to new DM1 families.

METHODS: The authors measured the size of the DM1 CTG repeat in blood DNA derived from a large number of individuals in DM1 families, including distant and unaffected relatives.

RESULTS: It was determined that DM1 premutation alleles can be identified both in distant relatives of DM1 probands and more rarely in unaffected spouses. These premutation alleles are not directly associated with a clinical phenotype in the carrier but are highly unstable and liable to expand in succeeding generations, particularly when transmitted by a man. In addition, the authors observed occasional expansion-biased instability of alleles within the high end of the normal size range.

CONCLUSIONS: Individuals carrying premutation alleles are at high risk of having affected offspring within a limited number of generations. Such data indicate that premutation alleles cannot be the long-term source of new DM1 families, which must ultimately arise from mutations of alleles within the upper normal size range.

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