Interpretation of Test Results

The analysis of gene mutations and protein determinations has greatly improved diagnosis, carrier detection, and prenatal counseling. The multiplex PCR deletion test will confirm the clinical diagnosis in approximately 65% of affected DMD and BMD patients. A major advantage of the Southern blot analysis is the detection of an additional 5% to 8% of patients with duplications. The standard multiplex PCR test detects deletions but not duplications. However, if there is any question of the diagnosis after negative results by deletion and duplication molecular testing, western blot analysis of the dystrophin protein should be performed on a muscle biopsy specimen.

When gene dosage testing indicates that the mother does not have the deletion present in the affected child, she still has an uncertain risk of carrier status, due to the possibility of germline mosaicism.16 Cases of germline mosaicism in DMD have been reported, in which a deletion is transmitted to more than one offspring by a mother who shows no evidence of the mutation in her somatic cells. Cases of germline mosaicism have important counseling implications. First and most obvious is the need to perform carrier studies on all female siblings of affected males, regardless of the outcome of testing for the mother. Furthermore, a negative deletion result in a mother does not rule out a recurrence risk for future pregnancies, and prenatal diagnosis still should be offered. The exact recurrence risk in germline female carriers is unknown because the risk is related to the size of the mutant clone in the mosaic mother. However, in these cases the recurrence risk for subsequent pregnancies is significantly increased relative to what had initially been perceived as a new mutation with a low recurrence risk. It has been estimated that mothers of apparently sporadic DMD cases have an approximate 15% recurrence risk in future pregnancies.

Linkage analysis can provide valuable information but is limited by the possibility of recombination between the polymorphic marker and the unknown mutation, the presence of sporadic mutations, and unavailability of family members. The intragenic recombination rate over the entire length of the DMD gene is estimated to be as high as 12%. The high recombinational error rate can be partially overcome by using microsatellite markers throughout the gene. Linkage analysis results often are extremely limited for extended family members of isolated cases of DMD/BMD, due to the possibility of the occurrence of a new mutation. Linkage analysis indicates only whether the female at risk inherited the same X chromosome as the affected male, not whether she is a carrier of a defective gene. Furthermore, since the gene mutation remains unidentified, a correct clinical diagnosis is essential. This is extremely important with patients presenting with the milder BMD, since this phenotype can overlap with other neuromuscular disorders.

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