Key result
Dystrophin exon 48 deletions exhibit highly variable phenotypes, manifesting as Duchenne muscular dystrophy in ~60%.
Observational
The high phenotypic variability of identical dystrophin gene mutations suggests that the clinical success of exon skipping therapy for Duchenne muscular dystrophy may be unpredictable.
High phenotypic variability in dystrophin deletions may render exon-skipping outcomes unpredictable; leaves open identification of modifiers before therapy personalization.
3 , . . 1 , . . 1,2 Analysis of phenotype expressions of deletions in the dystrophin gene in terms of efficiency of exon skipping as a method for treatment of hereditary dystrophinopathies Duchenne muscular dystrophy (DMD) is a common genetic disease caused by a mutation of the dystrophin gene. It leads to death in childhood. At the time of writing this paper, patients had access to supportive therapy only. However, DMD treatment methods are actively being developed. Exon skipping is a promising method. Exon skipping involves restoration of the reading frame within a gene by inducing alternative splicing. This leads to synthesis of truncated but still functional dystrophin. The paper assesses the functionality of the truncated forms of dystrophin resulting from correction of nonsense mutations and internal exon indels by exon-skipping technique. The assessment was made based on data on the phenotype of carriers of mutations in the dystrophin gene taken from the Leiden Open Variation Database (LOVD). It was revealed that the same mutation could manifest itself as a variety of phenotypes. This, perhaps, is as a result of the patients having different genetic background. For example, deletion of exon 48, for which there is 97 records in LOVD, resulted in asymptomatic diseases in 2 % of cases, Duchenne muscular dystrophy in 60 %, Becker muscular dystrophy (characterized by milder symptoms than DMD) in 12 % and intermediate phenotype in 26 % of cases. High phenotypic variability of mutations of the dystrophin gene raises the issue of limits of applying exon skipping for treatment of inherited myopathies.
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Zotova et al. (2016) conducted an observational in Duchenne and Becker muscular dystrophy. Deletions in the dystrophin gene was evaluated on Phenotypic manifestation of dystrophin gene deletions. Deletions in the dystrophin gene exhibit high phenotypic variability, with exon 48 deletion manifesting as Duchenne muscular dystrophy in 60% of cases, Becker muscular dystrophy in 12%, and asymptomatic in 2%.
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