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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

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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.

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Acknowledgments

The authors would like to thank the patients and their parents for their cooperation. We also would like to thank Ramak Heidari, Neda Anisi, and Samira Anisi, the Iranian Muscular Dystrophy Association members for their assistance in the process of data collection.

Funding

This research is supported by a grant from Tehran University of Medical Sciences (TUMS). The funding organization had no role in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the article and the decision to submit the article for publication.

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Authors and Affiliations

  1. Pediatrics Center of Excellence, Department of Pediatric Neurology, Children’s Medical Center, Tehran University of Medical Sciences, Bagherkhan St, Tehran, 1419733141, Iran

    Gholamreza Zamani, Sayna Bagheri, Kamyar Moradi, Ali Reza Tavasoli, Mahmoud Mohammadi, Reza Shervin Badv & Morteza Heidari

  2. Prenatal Diagnosis and Genetic Research Center, Dastgheib Hospital, Shiraz University of Medical Sciences, Shiraz, Iran

    Ali Hosseini Bereshneh

  3. Department of Medical Genetics, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

    Ali Hosseini Bereshneh

  4. Department of Pediatric Neurology, Golestan Medical, Educational, and Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

    Reza Azizi Malamiri

  5. Faculty of Medicine, Students’ Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran

    Sayna Bagheri & Kamyar Moradi

  6. Pediatrics Center of Excellence, Department of Pediatric Neurology, Children’s Medical Center, Growth and Development Research Center, Tehran University of Medical Sciences, Tehran, Iran

    Mahmoud Reza Ashrafi

  7. Department of Physical Medicine and Rehabilitation, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran

    Masood Ghahvechi Akbari

  8. Department of Pediatric Neurology, Vali-e-Asr Hospital, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran

    Morteza Heidari

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  1. Gholamreza Zamani
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  2. Ali Hosseini Bereshneh
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  3. Reza Azizi Malamiri
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Correspondence to Morteza Heidari.

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Zamani, G., Hosseini Bereshneh, A., Azizi Malamiri, R. et al. The First Comprehensive Cohort of the Duchenne Muscular Dystrophy in Iranian Population: Mutation Spectrum of 314 Patients and Identifying Two Novel Nonsense Mutations. J Mol Neurosci 70, 1565–1573 (2020). https://doi.org/10.1007/s12031-020-01594-9

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