Novel Intronic Mutations Introduce Pseudoexons in DMD That Cause Muscular Dystrophy in Patients

Area of Science:

• Genetics
• Molecular Biology
• Human Diseases

Background:

• Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are genetic disorders caused by mutations in the DMD gene.
• Over 4,600 DMD gene mutations are known, but only 33 are deep intronic, making them rare and challenging to detect.

Purpose of the Study:

• To identify novel deep intronic mutations in the DMD gene responsible for DMD and BMD.
• To evaluate the efficacy of combining whole-exome sequencing (WES) with cDNA analysis for variant detection in the large DMD gene.

Main Methods:

• Utilized a combination of whole-exome sequencing (WES), complementary DNA (cDNA) sequencing, and target DNA sequencing.
• Analyzed DNA and RNA samples from patients diagnosed with DMD and BMD.

Main Results:

• Identified three novel deep intronic mutations (IVS11 + 17811C > G, IVS21 + 3252A > G, IVS40 + 362A > G) in DMD patients.
• Detected one previously reported deep intronic mutation (IVS62-285A > G) in a BMD patient.
• These mutations resulted in pseudoexon insertions, leading to truncated and non-functional dystrophin protein.

Conclusions:

• The study identified three novel and one reported deep intronic DMD mutations associated with DMD/BMD.
• Emphasizes the necessity of integrating WES with cDNA-based methods for comprehensive variant detection in the complex DMD gene.