The First Comprehensive Cohort of the Duchenne Muscular Dystrophy in Iranian Population: Mutation Spectrum of 314 Patien
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The First Comprehensive Cohort of the Duchenne Muscular Dystrophy in Iranian Population: Mutation Spectrum of 314 Patients and Identifying Two Novel Nonsense Mutations Gholamreza Zamani 1 & Ali Hosseini Bereshneh 2,3 & Reza Azizi Malamiri 4 & Sayna Bagheri 1,5 & Kamyar Moradi 1,5 & Mahmoud Reza Ashrafi 6 & Ali Reza Tavasoli 1 & Mahmoud Mohammadi 1 & Reza Shervin Badv 1 & Masood Ghahvechi Akbari 7 & Morteza Heidari 1,8 Received: 6 March 2020 / Accepted: 14 May 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract 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. Keywords Duchenne muscular dystrophy . MLPA . Dystrophin mutation . NGS . Iranian patients
Introduction Duchenne muscular dystrophy (DMD) is the most common muscular disease in children affecting 15.9–19.5 per 100,000
live male births (Ryder et al. 2017). DMD occurs due to mutations in the dystrophin gene, which is located on the X chromosome in the Xp21 region (Vainzof et al. 2008). The dystrophin gene is one of the longest human genes, spans more
* Morteza Heidari [email protected]
5
Faculty of Medicine, Students’ Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
1
Pediatrics Center of Excellence, Department of Pediatric Neurology, Children’s Medical Center, Tehran University of Medical Sciences, Bagherkhan St, Tehran 1419733141, Iran
6
Pediatrics Center of Excellence, Department of Pedia
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