The First Comprehensive Cohort of the Duchenne Muscular Dystrophy in Iranian Population: Mutation Spectrum of 314 Patients and Identifying Two Novel Nonsense Mutations

Mutations in the dystrophin gene could cause Duchenne muscular dystrophy (DMD), which is the most common muscular disorder in pediatrics. Considering the growing evidence on appropriateness of gene therapies for DMD, precise genetic diagnosis seems essential. Hence, we conducted a study to determine mutational patterns in Iranian children with DMD. To detect all probable large mutations in the dystrophin gene, 314 DMD patients were evaluated using the multiplex ligation-dependent probe amplification (MLPA). Subjects who were MLPA-negative underwent the next generation sequencing (NGS) to identify potential point mutations. MLPA detected deletions (79.93%) and duplications (5.41%) along the dystrophin gene of 268 patients. Distribution of large mutations was heterogeneous and followed hotspot pattern throughout the gene. From 46 patients who were MLPA-negative, 43 exhibited point mutations including nonsense in 7.64%, frameshifts in 4.77%, splicing in 0.96%, and missense variations in 0.32% of participants. Most of the point mutations were located between exons 19 and 40. In three patients (1%), no mutation was found using either MLPA or NGS. Two subjects had novel nonsense mutations (L1675X and E1199X) in their dystrophin gene, which were considered as the possible reason for elimination of major domains of the gene. The results of this study provided invaluable information regarding the distribution of various large and small mutations in Iranian individuals with DMD. Besides, the novel nonsense mutations L1675X and E1199X were identified within the highly conserved residues, leading to elimination of significant domains of the dystrophin gene.