Ali Khanbazi
1,2 
, Farzane Zare Ashrafi
1,2 , Masoumeh Akbari Kelishomi
1, Raziye Rezvani Rezvandeh
1,2 , Maryam Azad
1, Fatemeh Ahangari
1, Mahsa Fadaee
1, Shima Dehdahsi
1, Mina Makvand
1, Banafsheh Salmani
1, Zohreh Vahidi
1, Mahdieh Kooshki
1, Atiyeh Ahmadpour
1, Elmira Shiuokhi
1, Armita Ghaderi
1, Mahsa Tahmasebivand
1,2, Fariba Afroozan
1, Khadijeh Noudehi
1, Fatemeh Fatehi
1, Shima Zamanian Najafabadi
1, Elahe Jafarnataj
2, Shahriar Nafissi
3, Haleh Habibi
4, Maryam Taghdiri
5, Bahram Haghi Ashtiani
6, Gholamreza Zamani
7, Farzad Fatehi
8, MohammadKazem Bakhshandeh
9, Farshid Parvini
10, Payman Jamali
11, Kimia Kahrizi
2, Ariana Kariminejad
1, Hossein Najmabadi
1,2* 1 Kariminejad - Najmabadi Pathology & Genetics Center, Tehran, Iran
2 Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
3 Department of Neurology, Neuromuscular Research Center, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran
4 Hamedan University of Medical Science, Hamedan, Iran
5 Shiraz Genetic Counseling Center, Welfare Office, Shiraz, Iran
6 Department of Neurology, Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran
7 Tehran University of Medical Sciences, Children’s Medical Center, Tehran, Iran
8 Iranian Center of Neurological Research, Neuroscience Institute, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran
9 Pediatric Neurology Center of Excellence, Department of Pediatric Neurology, Mofid Children Hospital
10 Department of Biology, Faculty of Basic Sciences, Semnan University, Semnan, Iran
11 Mashhad Medical Genetic Counseling Center, Mashhad, Iran
Abstract
Introduction: Mutations in the X-linked dystrophin gene (DMD) cause Duchenne (DMD) and Becker muscular dystrophies (BMD), severe and milder forms of inherited progressive muscle deterioration, for which genetic testing is essential to confirm diagnosis, genetic counseling, and eligibility for molecular therapies.
Objective: This study aimed to elucidate the pattern of DMD mutations in a large cohort of Iranian patients and assess the applicability of mutation-specific therapies.
Methods: We retrospectively analyzed 2162 individuals referred to the Kariminejad - Najmabadi Pathology & Genetics Center (KNPGC) for DMD mutation testing. The samples consisted of 1093 males for diagnostic testing, 946 females for carrier detection, and 123 fetuses for prenatal assessments. Most cases were first examined using multiplex ligation-dependent probe amplification (MLPA), with negative results further evaluated by next-generation sequencing (NGS) or Sanger sequencing.
Results: Among 1093 males tested for diagnostic purposes, 608 (55.63%) were positive for DMD mutations. Among these positive cases, 470 deletions (77.30%) and 81 duplications (13.32%) were identified. Point mutations were identified in 55 patients (9.05%), with nonsense and frameshift variants being the most prevalent. Mutations predominantly affected exons 44–55 (44.17%) and 3–27 (35.75%). Notably, 69.09% of point mutations were located within the proximal 40 exons of the gene. Additionally, DP427 isoforms were disrupted in all patients, while shorter isoforms (DP116, DP71) were rarely affected. Applicability of mutation-specific therapies indicated that 49.34% of patients could theoretically benefit from exon-skipping strategies, 29.60% were eligible for currently approved therapies, and 3.45% with nonsense mutations could benefit from a read-through therapy.
Conclusion: This study provides an overview of DMD mutations in a large cohort of patients referred for testing, highlighting mutation patterns and the potential applicability of molecular therapies.