Genetic Profile of the Dystrophin Gene Reveals New Mutations in Colombian Patients Affected with Muscular Dystrophinopathy

Abstract

Background

Duchenne and Becker muscular dystrophies (DMD/BMD) are the most common human dystrophinopathies with recessive X-linked inheritance. Dystrophin gene deletions and duplications are the most common mutations, followed by point mutations. The aim of this study is to characterize the mutational profile of the dystrophin gene in Colombian patients with DMD/BMD.

Material and Methods

Mutational profiling was determined in 69 affected patients using Sanger sequencing, next-generation sequencing (NGS) and/or multiplex ligation dependent-probes amplification (MLPA). Genetic variants were classified according to molecular consequence and new variants were determined through database and literature analysis.

Results

Mutational profile in affected patients revealed that large deletions/duplications analyzed by MLPA accounted for 72.5% of all genetic variations. By using Sanger sequencing or NGS, we identified point mutations in 15.9% and small deletions in 11.6% of the patients. New mutations were found, most of them were point mutations or small deletions (10.1%).

Conclusion

Our results described the genetic profile of the dystrophin gene in Colombian patients with DMD and contribute to efforts to identify molecular variants in Latin American populations. For our population, 18.8% of cases could be treated with FDA or MDA approved molecular therapies based on specific mutations. These data contribute to the establishment of appropriate genetic counseling and potential treatment.

Keywords:

• Duchenne–Becker muscular dystrophy
• DMD
• MLPA
• next-generation sequencing
• target molecular therapy
• exon skipping
• mutation

Abbreviations

DMD/BMD, Duchenne and Becker muscular dystrophies; NGS, next-generation sequencing; MLPA, multiplex ligation dependent-probes amplification; NHEJ, the non-homologous end joining mechanism; NAHR, the non-allelic homologous recombination; ORF, open reading frame; ASD, α-syntrophin; DBD, dystrobrevin; PTC, premature termination codons; NMD, Nonsense Mediated Decay system; AIMs Ancestry informative markers.

Ethics Approval and Consent to Participate

All experimental procedures were approved by the Ethics Committee of the Universidad del Rosario. The study followed the guidelines of the Declaration of Helsinki (Approved CEI-AMH002-000185). All participants provided informed consent to take part in this study and for clinical attention in the private laboratory Genética Molecular de Colombia.

Acknowledgments

We thank Genética Molecular de Colombia and Universidad del Rosario for providing all the data and infrastructure necessary for carrying out this study.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.

Additional information

Funding

Funding was not applicable. Data was obtained for molecular diagnosis of analyzed patients. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.