Risk assessment and genetic counseling in families with Duchenne muscular dystrophy

Abstract

The Duchenne Muscular dystrophy (DMD) is the most frequent muscle disorder in childhood caused by mutations in the Xlinked dystrophin gene (about 65% deletions, about 7% duplications, about 26% point mutations and about 2% unknown mutations). The clinically milder Becker muscular dystrophy (BMD) is allelic to DMD. About 33% of all patients are due to de novo mutations and germ line mosaicism is frequently observed. While in earlier studies equal mutation rates in males and females had been reported, a breakdown by mutation types can better explain the sex ratio of mutations: Point mutations and duplications arise preferentially during spermatogenesis whereas deletions mostly arise in oogenesis. With current analytical methods, the underlying mutation can be identified in the great majority of cases and be used for carrier detection. However, in families with no mutation carrier available, the genetic model to be used for counselling of relatives can be quite complex.

Keywords: Becker muscular dystrophy; Duchenne muscular dystrophy; dystrophin gene; genetic model; germ line mosaicism; molecular genetic diagnosis.

Table 2.

Mutation-selection balance for an X-linked lethal disease like DMD.

Figure 1.

Mother of an affected boy is carrier because her mother is carrier.

Figure 2.

Left pedigree: mother of an affected boy is carrier as a result of a de novo mutation in one of her parents' gametes (1-g = proportion of de novo mutations occurring in the meiosis; u = female mutation rate; v = male mutation rate). Right pedigree: the affected boy is a de novo mutation.

Figure 3.

Left and middle pedigree: the mother of an affected boy is carrier because her father (a) of her mother (b) carried a germline mosaic (f = segregation in germline mosaics; g = probability of de novo mutations in the mitosis; u = female mutation rate; v = male mutation rate). Right pedigree: a mother of an affected boy carries a germline mosaic.