Genotype–Phenotype Correlations in Duchenne and Becker Muscular Dystrophy Patients from the Canadian Neuromuscular Disease Registry

Abstract

Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disorder generally caused by out-of-frame mutations in the DMD gene. In contrast, in-frame mutations usually give rise to the milder Becker muscular dystrophy (BMD). However, this reading frame rule does not always hold true. Therefore, an understanding of the relationships between genotype and phenotype is important for informing diagnosis and disease management, as well as the development of genetic therapies. Here, we evaluated genotype–phenotype correlations in DMD and BMD patients enrolled in the Canadian Neuromuscular Disease Registry from 2012 to 2019. Data from 342 DMD and 60 BMD patients with genetic test results were analyzed. The majority of patients had deletions (71%), followed by small mutations (17%) and duplications (10%); 2% had negative results. Two deletion hotspots were identified, exons 3–20 and exons 45–55, harboring 86% of deletions. Exceptions to the reading frame rule were found in 13% of patients with deletions. Surprisingly, C-terminal domain mutations were associated with decreased wheelchair use and increased forced vital capacity. Dp116 and Dp71 mutations were also linked with decreased wheelchair use, while Dp140 mutations significantly predicted cardiomyopathy. Finally, we found that 12.3% and 7% of DMD patients in the registry could be treated with FDA-approved exon 51- and 53-skipping therapies, respectively.

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

“…This indicates the potential presence of reporting bias in the clinical reports [ 29 ]. To note, in the aggregate of the data collected from the two databases but without those obtained from the literature, 11.05% of individuals with in-frame large deletions developed severe phenotype, which is comparable with the numbers indicated by previous reports ( Figures S5 and S6 ) [ 7 , 8 , 10 , 20 , 30 ].…”

Genetic Landscape of Dystrofin Gene Deletions and Duplications From Turkey: A Single Center Experience

“…DMD and BMD are the most common hereditary neuromuscular disease group of the childhood caused by the mutations which cause a defect in the synthesis of the fully-functional 427-kDa dystrophin protein (1)(2)(3)(4)(5)(6)(7)(8)(9). They make up approximately 50% of the neuromuscular diseases in our country (10).…”

“…Approximately twothirds of the considerably complex mutations in BMD/DMD are large deletions or duplications in one or more exons while the remainder is minor deletions, insertions, point mutations, and splicing mutations (1)(2)(3)(4)(5)(6)(7)(8)(9). Although the mutation frequency and spectrum depend on the country, DNA/RNA-based therapeutic approaches have rendered population-based genetic features more important in dystrophinopathies which still lack a curative treatment, especially in the last decade (5)(6)(7)(8)(9). Quantitative techniques such as microarray-based comparative genomic hybridization (array-CGH) and the more frequently utilized Multiple Ligation Probe Assay (MLPA) which detect the deletions and duplications are the first choices for the diagnosis of the disease (1)(2)(3).…”

Understanding Neuromuscular Health and Disease: Advances in Genetics, Omics, and Molecular Function

“…However, even if great progress has been made during the last two decades in different subgroups of neuromuscular disorders, there are still numerous challenges to resolve, such as the optimization of therapeutic knock-down strategies [3], targeting specific muscles and/or tissues of the nervous system [1], identifying genetic modifiers that can impair a therapeutic strategy [2], targeting common pathways being affected in different patient subgroups for a given disease [4,5], or understanding the impact of neuromuscular disorders on other tissues that could be affected but may be understudied. This Special Issue, entitled "Understanding Neuromuscular Health and Disease: Advances in Genetics, Omics, and Molecular Function", encompasses some 15 publications from colleagues working on a diverse range of neuromuscular diseases, including Duchenne muscular dystrophy [6][7][8][9], facioscapulohumeral dystrophy [3,10,11], amyotrophic lateral sclerosis [4,5,12], spinal muscular atrophy [2], Emery-Dreifuss muscular dystrophy [13], and rheumatoid arthritis [14]. Looking across diseases, several themes are recurrent, such as the efforts to identify genotype-phenotype correlations in DMD [6,7,9] and ALS [4,5], the quest for effective biomarkers in many neuromuscular conditions [2,8,10,14], and the use of genomic and multi-omic approaches towards better ways to identify biomarkers and to understand disease [10,12,13].…”

“…The search for genotype-phenotype correlations can be aimed at the improved understanding of disease [4,5,7,9], but may also be relevant to potential therapeutic outcomes [6]. Of relevance to this Special Issue are genotype-phenotype correlations in DMD [6,7,9] and in ALS [4,5].…”