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Genetic Analysis of Forty MLPA-Negative Duchenne Muscular Dystrophy Patients by Whole-Exome Sequencing

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Abstract

This manuscript aimed to determine the underlying point mutations causing Duchenne muscular dystrophy (DMD) in a heterogeneous group of Iranian patients, who are clinically suspected. Whole-exome sequencing was utilized to detect disease-causing variants in 40 MLPA-negative DMD patients. Disease-causing variants were detected in the DMD gene in 36/40 of the patients (90%), and 4/40 of them (10%) remained undiagnosed. WES analysis revealed that nonsense variant was the most common type in our study (23/36 of the cases). Besides, 12/36 of the cases had frameshift variant, and one of the patients had a likely pathogenic splice variant in the DMD gene. Carrier testing revealed that 21/40 of the mothers had the identified variant. Therefore, most variants were inherited (58.3%), while 19/40 were de novo (41. 7%). The present study has demonstrated the importance of performing WES to detect disease-causing point mutations in MLPA-negative DMD patients and to identify carrier females. Due to regulatory challenges, the clinical development of therapeutic approaches is time-consuming and may not be available to all patients shortly. Therefore, it appears that the techniques used to accurately detect disease-causing variants in carrier mothers are a more efficient solution to prevent the increased prevalence of DMD.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

The authors would like to thank the patients and their parents for their cooperation. We also would like to thank all the Iranian Muscular Dystrophy Association members for their assistance in the process of data collection.

Funding

This research is supported by a grant from the 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.

Author information

Author notes

  1. Gholam Reza Zamani and Mohammad Farid Mohammadi have an equal contribution as the first authors.

Authors and Affiliations

  1. Department of Pediatric Neurology, Pediatrics Center of Excellence, Children’s Medical Center, Myelin Disorders Clinic, Tehran University of Medical Sciences, Tehran, Iran

    Gholam Reza Zamani, Ali Reza Tavasoli, Mahmoud Reza Ashrafi, Homa Ghabeli, Elham Pourbakhtyaran, Roya Haghighi & Morteza Heidari

  2. Department of Cell and Molecular Sciences, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran

    Mohammad Farid Mohammadi

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

    Sareh Hosseinpour

  4. Department of Pediatric Neurology, School of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran

    Seyyed Mohammad Mahdi Hosseiny

  5. Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Postal Code, Jalah-Al Ahmad Hwy, 14117-1316, Tehran, Iran

    Pouria Mohammadi

  6. Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, USA

    Ali Reza Tavasoli

Authors
  1. Gholam Reza Zamani
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  2. Mohammad Farid Mohammadi
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  4. Mahmoud Reza Ashrafi
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Contributions

GRZ and MFM conceived and designed the experiments. MFM, PM, MH, ART, RH, EPB, HGH, and MRA conducted the experiments. PM, GHZ, MH, and MFM analyzed and interpreted the data. PM and MFM contributed reagents/materials/analysis tools. MFM, PM, MH, SH, and SMH wrote the paper. All authors reviewed the manuscript.

Corresponding authors

Correspondence to Pouria Mohammadi or Morteza Heidari.

Ethics declarations

Ethics Approval and Consent to Participate

All the patients presented to the Children’s Medical Centre, Tehran University of Medical Sciences (TUMS) or were registered on the Iranian Muscular Dystrophy Association registry system. Written consent was obtained from all the enrolled patients or their respective legal guardians. The research was approved by the local medical ethics committee of TUMS (IRB code: IR.TUMS.MEDICINE.REC.1396.3568). Adherence to the World Medical Association Declaration of Helsinki and its successive revisions was considered in this research.

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Written informed consent was obtained from the patient for publication of this case report and any accompanying images.

Competing Interests

The authors declare no competing interests.

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Zamani, G.R., Mohammadi, M.F., Tavasoli, A.R. et al. Genetic Analysis of Forty MLPA-Negative Duchenne Muscular Dystrophy Patients by Whole-Exome Sequencing. J Mol Neurosci 72, 1098–1107 (2022). https://doi.org/10.1007/s12031-022-01980-5

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  • DOI: https://doi.org/10.1007/s12031-022-01980-5

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