Genotypes and phenotypes of DMD small mutations in Chinese patients with dystrophinopathies

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.