Genotype-Phenotype Correlation among patients with Dystrophinopathies

Objective: To correlate the site and size of dystrophin gene deletion with the clinical picture in patients with dystrophinopathies. Design: The dystrophin gene is one of the largest known genes. More than half of the dystrophinopathy cases are associated with intrageneic deletions. The importance of the study arises from the fact that dystrophin cDNA probes provide a direct method of genetic diagnosis. This is the first study in an Arab population and only the second to use a three multiplex PCR method. Setting: Kuwait Medical Genetic Centre and Faculty of Medicine –Ain Shams University, Egypt Subjects and Methods: Fifty-two patients with dystrophinopathies (50 with Duchenne muscular dystrophy( DMD) and 2 with Becker muscular dystrophy (BMD) from both Kuwait and Egypt were ascertained. Dystrophin gene deletions were detected using three multiplex reactions. Results: DNA analysis showed that 71.4% of the patients had deletion of the dystrophin gene while 28.6% showed no deletion. 24.5% had two deleted exons while 14.3% had only one deleted exon. The most common deleted exons among the Kuwaiti patients were 81,45 & 48 while exons 19, 45, 48 & 51 were found more commonly deleted among the Egyptian patients. The onset of walking was not changed by the number of exons deleted except when five exons were deleted. However, delayed onset of walking was observed when exon 48,51 and 45 were deleted (r=0.6078, and p=0.110). On the other hand, the average onset of weakness was neither correlated to the number of the exons deleted or to the deletion sites. Similar results were obtained regarding the average onset of wheel chair dependency. There was a slightly lower IQ with deletion of exons 48,45 and 12 but in general there is no correlation between the IQ and the site or the frequency of the deletion. Study of the intragenic deletions in 25 exons of the dystrophin gene using three different multiplex PCR sets revealed that 78%, 76% and 12% of DMD patients had deletion of each of the three sets separately. With all three sets together, the detection of deletion rate was increased to 86%. Fifty percent of the deleted exons were located in the distal hot spot, 8% in the proximal hot spot while 42% were scattered over both sides of the hot spot. Conclusion: No significant correlation was found between the size/site of the dystrophin deletions and the clinical severity. A multi centre larger study is recommended for a better understanding of the genotype-phenotype correlation.