Two hot spots of recombination in the DMD gene correlate with the deletion prone regions

Abstract

Genetic mapping has indicated that meiotic recombination occurs about 4 time more frequently in the dystrophin gene than expected on the basis of its length. To detect where recombinations occur within the gene, we have studied the CEPH families panel using highly polymorphic microsatellite markers located at the ends of the gene or flanking the major deletion hot spot in intron 44. We found a major hot spot of recombination between markers STR44 and STR50(1), i.e., between exons 44 and 51. Within this hot spot, a peak of recombination was located in the large intron 44. A second minor recombination prone region was found between DXS 206, (XJ, in the large intron 7) and the 5' end of the DMD gene. The distribution of the recombination events in the gene of healthy individuals was very similar to that of deletion breakpoints in DMD/BMD patients, suggesting that the two phenomenon may share a common mechanism. These results should also improve efficiency and accuracy of linkage analysis applied to carrier detection and prenatal diagnosis. In particular, if markers located at the very 3' end of the gene are not informative, the highly polymorphic ones located between exons 50 and 60 can be used instead of presently available extragenic markers, with a very low risk of diagnostic error due to recombination.

Haplotype-based approach for noninvasive prenatal tests of Duchenne muscular dystrophy using cell-free fetal DNA in maternal plasma

“…The recombination frequency expected for the dystrophin gene based on its size (2.4 Mb) is 2.4%; however, the observed frequency was higher (6-10%) than expected according to previous reports. [32][33][34][35] How to accurately infer the fetal inherited allele for recombination cases remains an area for future effort. With the development of new bioinformatics models and improvements in haplotyping, we believe that noninvasive prenatal testing could provide a preliminary screening approach for most at-risk pregnant women.…”

Human X-chromosomal lineages in Europe reveal Middle Eastern and Asiatic contacts

“…37 However, the dys44 segment lies in an intronic region in the middle of the large (2.4 Mb) dystrophin gene, and has a level of genetic diversity typical of neutral variation, and satisfies neutral expectations when tested with Tajima's 38 D parameter. 21 Furthermore, dys44 is found in a region of the Xchromosome that experiences a high recombination rate, 39 and is thus very unlikely to be affected by selection on the neighboring loci. Secondly, because of the X-chromosome's mode of inheritance, the geographic structure of its genetic diversity has been relatively more affected by female, rather than male, migration.…”

Characterization of deletion breakpoints in patients with dystrophinopathy carrying a deletion of exons 45–55 of the Duchenne muscular dystrophy (DMD) gene

“…[2][3][4][5][6][7] Despite heterogeneity in both deletion size and location, two deletion 'hotspots' have been identified in DMD: a minor 'hotspot' including exons 2-19, and the major one involving exons 40-50 or 45-55. 2,4,5,7 Among deletions of variable sizes and locations found in DMD/ BMD patients, deletion of exons 45-55 (del45-55) in DMD has gained particular attention because an artificial dystrophin with del45-55 created by a multiple exon-skipping strategy could transform the DMD phenotype into the asymptomatic or milder BMD phenotype. 8 We reported three patients with del45-55 who presented with the phenotypes far from DMD.…”