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Published on: May 7, 2020
Genotypes and Phenotypes of DMD Small Mutations in Chinese Patients With Dystrophinopathies
Liang Wang1, Min Xu2,3, Huan Li1
1Department of Neurology, National Key Clinical Department and Key Discipline of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
Abstract:
Dystrophinopathies are a group of neuromuscular disorders resulting from mutations in DMD, including Duchenne muscular dystrophy (DMD), intermediate muscular dystrophy (IMD), and Becker muscular dystrophy (BMD). Herein, we present the characteristics of small mutations in Chinese patients with dystrophinopathies, and explore genotype-phenotype correlations. In our cohort, 115 patients with small mutations (18.49% of all patients) were included and DMD mutations were detected by either Sanger (53.91%) or next generation sequencing (46.09%). In total, 106 small mutations were detected, 28 of which (26.42%) had not been reported previously. The most common mutations were nonsense mutations (52.17%), followed by splicing (24.35%), frameshift (17.39%), and missense mutations (5.22%), in addition to a single untranslated region mutation (0.87%). We discovered distinct mutation characteristics in our patients, such as different positional distributions, indicating different exon skipping therapy strategies for small mutations in Chinese patients. Almost all patients (96.51%) with truncating or missense mutations, were covered by triple/double/single-exon skipping therapy; the most frequent single-exon skipping strategy was skipping exon 32, applicable for 8.51% of patients. Furthermore, splicing classification grades were correlated with phenotypes in nonsense mutations (P < 0.001), and serum creatinine levels differed significantly between DMD/IMD and BMD for patients ≤ 16 years old (P = 0.002). These observations can further aid prognostic judgment and guide treatment. In conclusion, the mutation characteristics and genotype-phenotype correlations in Chinese patients with dystrophinopathies and small mutations could provide insights into the molecular mechanisms of pathogenesis, diagnosis, and treatment designs.
Insights
Small mutations in the DMD gene cause dystrophinopathies in Chinese patients. Understanding these mutations and their links to disease severity can guide personalized exon skipping therapies and improve patient prognoses.
Area of Science:
- Genetics
- Neurology
- Molecular Biology
Background:
- Dystrophinopathies encompass neuromuscular disorders arising from mutations in the DMD gene, including Duchenne muscular dystrophy (DMD), intermediate muscular dystrophy (IMD), and Becker muscular dystrophy (BMD).
- Small mutations in the DMD gene represent a significant portion of dystrophinopathy cases, necessitating detailed characterization for effective management.
Purpose of the Study:
- To characterize small mutations in the DMD gene in a Chinese cohort of patients with dystrophinopathies.
- To explore genotype-phenotype correlations and identify potential therapeutic strategies based on mutation characteristics.
Main Methods:
- Sanger sequencing and next-generation sequencing were employed to detect DMD mutations in 115 patients.
- Mutation types were classified (nonsense, splicing, frameshift, missense), and their positional distributions analyzed.
- Genotype-phenotype correlations were assessed, including relationships between splicing grades, phenotypes, and serum creatinine levels.
Main Results:
- 106 small DMD mutations were identified, with 28 previously unreported.
- Nonsense mutations were most common (52.17%), followed by splicing (24.35%) and frameshift (17.39%) mutations.
- Distinct mutation characteristics and positional distributions were observed in the Chinese cohort, suggesting tailored exon skipping strategies, with exon 32 skipping being the most frequent single-exon strategy.
Conclusions:
- The study identified unique mutation profiles in Chinese patients with dystrophinopathies, informing personalized exon skipping therapy designs.
- Splicing classification grades correlated significantly with phenotypes in nonsense mutations, and serum creatinine levels differed between DMD/IMD and BMD in younger patients.
- These findings enhance prognostic judgment, guide treatment strategies, and offer insights into molecular pathogenesis and diagnosis for dystrophinopathies.
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