Molecular characterization of exonic rearrangements and frame shifts in the dystrophin gene in Duchenne muscular dystrophy patients in a Saudi community

Abstract

BackgroundIn individuals with Duchenne muscular dystrophy (DMD), exon skipping treatment to restore a wild-type phenotype or correct the frame shift of the mRNA transcript of the dystrophin (DMD) gene are mutation-specific. To explore the molecular characterization of DMD rearrangements and predict the reading frame, we simultaneously screened all 79 DMD gene exons of 45 unrelated male DMD patients using a multiplex ligation-dependent probe amplification (MLPA) assay for deletion/duplication patterns. Multiplex PCR was used to confirm single deletions detected by the MLPA.ResultsThere was an obvious diagnostic delay, with an extremely statistically significant difference between the age at initial symptoms and the age of clinical evaluation of DMD cases (t value, 10.3; 95% confidence interval 5.95–8.80, P < 0.0001); the mean difference between the two groups was 7.4 years. Overall, we identified 147 intragenic rearrangements: 46.3% deletions and 53.7% duplications. Most of the deletions (92.5%) were between exons 44 and 56, with exon 50 being the most frequently involved (19.1%). Eight new rearrangements, including a mixed deletion/duplication and double duplications, were linked to seven cases with DMD. Of all the cases, 17.8% had duplications with no hot spots. In addition, confirmation of the reading frame hypothesis helped account for new DMD rearrangements in this study. We found that 81% of our Saudi patients would potentially benefit from exon skipping, of which 42.9% had a mutation amenable to skipping of exon 51.ConclusionsOur study could generate considerable data on mutational rearrangements that may promote future experimental therapies in Saudi Arabia.Electronic supplementary materialThe online version of this article (10.1186/s40246-018-0152-8) contains supplementary material, which is available to authorized users.

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“…Furthermore, admixture among different geographical populations might increase genetic variations and perhaps create new genotypic combinations within non-isolated (or non-native) populations. 45 Thus, genetic variations among some Middle Eastern individuals (e.g., Barbarians in North Africa, Kurdish, Upper Egyptian) [46][47][48][49] should be handled with caution, as increased consanguinity, reproductive isolation, and admixture with native source populations (e.g., Black Africans, South Eastern Asians, Caucasians) have considerable roles in gene flow and founder effects in these populations. For instance, the frequency of the 677T allele is often reported to be high in Europeans and North Americans, to be low in East Asians and Africans, and to show geographical gradients in areas of Europe, North America, and India.…”

Patterns of Dystrophin Gene Deletion/Duplication in a Sample of Saudi Patients with Duchenne Muscular Dystrophy

“…Recently in 2018, A study done in Saudi Arabia by Elhawary et al, [19] the authors used multiplex PCR and MLPA to identify gene mutation, they found 46.3% deletions and 53.7% duplications in the DMD gene, they also identified seven previously undescribed large DMD rearrangements. These new mutations included mixed rearrangement, large deletion, large duplications and double duplications.…”

Computational cognitive modeling and validation of Dp140 induced alteration of working memory in Duchenne Muscular Dystrophy

“…Reduction in mean full scale intelligence quotient (FSIQ), by approximately one standard deviation, with respect to the population mean, has remained a consistent finding in the cognitive profile in these patients 5 . DMD is manifested by rearrangement events including deletion, duplication and point mutations in DMD gene which create a shift in the reading frame that result in non-functional dystrophin protein 6,7 . DMD gene locus produces full length and short sized dystrophin products from seven distinct promoters.…”