scholarly journals A Genotype-Phenotype Correlation Study of Exon Skip-Equivalent In-Frame Deletions and Exon Skip-Amenable Out-of-Frame Deletions across the DMD Gene to Simulate the Effects of Exon-Skipping Therapies: A Meta-Analysis

2021 ◽  
Vol 11 (1) ◽  
pp. 46
Author(s):  
Saeed Anwar ◽  
Merry He ◽  
Kenji Rowel Q. Lim ◽  
Rika Maruyama ◽  
Toshifumi Yokota

Dystrophinopathies are caused by mutations in the DMD gene. Out-of-frame deletions represent most mutational events in severe Duchenne muscular dystrophy (DMD), while in-frame deletions typically lead to milder Becker muscular dystrophy (BMD). Antisense oligonucleotide-mediated exon skipping converts an out-of-frame transcript to an in-frame one, inducing a truncated but partially functional dystrophin protein. The reading frame rule, however, has many exceptions. We thus sought to simulate clinical outcomes of exon-skipping therapies for DMD exons from clinical data of exon skip-equivalent in-frame deletions, in which the expressed quasi-dystrophins are comparable to those resulting from exon-skipping therapies. We identified a total of 1298 unique patients with exon skip-equivalent mutations in patient registries and the existing literature. We classified them into skip-equivalent deletions of each exon and statistically compared the ratio of DMD/BMD and asymptomatic individuals across the DMD gene. Our analysis identified that five exons are associated with significantly milder phenotypes than all other exons when corresponding exon skip-equivalent in-frame deletion mutations occur. Most exon skip-equivalent in-frame deletions were associated with a significantly milder phenotype compared to corresponding exon skip-amenable out-of-frame mutations. This study indicates the importance of genotype-phenotype correlation studies in the rational design of exon-skipping therapies.

2020 ◽  
Vol 10 (3) ◽  
pp. 111 ◽  
Author(s):  
Omar Sheikh ◽  
Toshifumi Yokota

Currently, Duchenne muscular dystrophy (DMD) and the related condition Becker muscular dystrophy (BMD) can be usually diagnosed using physical examination and genetic testing. While BMD features partially functional dystrophin protein due to in-frame mutations, DMD largely features no dystrophin production because of out-of-frame mutations. However, BMD can feature a range of phenotypes from mild to borderline DMD, indicating a complex genotype–phenotype relationship. Despite two mutational hot spots in dystrophin, mutations can arise across the gene. The use of multiplex ligation amplification (MLPA) can easily assess the copy number of all exons, while next-generation sequencing (NGS) can uncover novel or confirm hard-to-detect mutations. Exon-skipping therapy, which targets specific regions of the dystrophin gene based on a patient’s mutation, is an especially prominent example of personalized medicine for DMD. To maximize the benefit of exon-skipping therapies, accurate genetic diagnosis and characterization including genotype–phenotype correlation studies are becoming increasingly important. In this article, we present the recent progress in the collection of mutational data and optimization of exon-skipping therapy for DMD/BMD.


2018 ◽  
Vol 63 (10) ◽  
pp. 1041-1048 ◽  
Author(s):  
Ruiyi Yuan ◽  
Junfei Yi ◽  
Zhiying Xie ◽  
Yimeng Zheng ◽  
Miao Han ◽  
...  

2019 ◽  
Vol 186 ◽  
pp. 107720
Author(s):  
Zhirong Wang ◽  
Chonglin Chen ◽  
Limei Sun ◽  
Aiyuan Zhang ◽  
Chengxi Liu ◽  
...  

2012 ◽  
Vol 23 (7) ◽  
pp. 781-790 ◽  
Author(s):  
Zacharias Aloysius Dwi Pramono ◽  
Keng Boon Wee ◽  
Jian Li Wang ◽  
Yi Jun Chen ◽  
Qian Bin Xiong ◽  
...  

2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Sebastien P. F. JanssensdeVarebeke ◽  
Julie Moyaert ◽  
Erik Fransen ◽  
Britt Bulen ◽  
Celine Neesen ◽  
...  

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