Copy number variation analysis increases the diagnostic yield in muscle diseases

Area of Science:

• Genetics
• Molecular Biology
• Neurology

Background:

• Skeletal muscle disorders present diagnostic challenges.
• Next-generation sequencing (NGS) is a powerful tool for genetic analysis.
• Copy number variants (CNVs) are a significant source of genetic variation.

Purpose of the Study:

• To enhance the diagnostic yield for skeletal muscle disorders by analyzing copy number variants (CNVs).
• To identify novel genetic causes of myopathies using comprehensive sequencing data analysis.

Main Methods:

• Utilized four bioinformatic tools to analyze CNVs from NGS data in patients with undiagnosed muscle diseases.
• Verified detected CNVs using array comparative genomic hybridization or PCR.
• Interpreted the clinical significance of verified CNVs by integrating genetic and clinical data.

Main Results:

• Identified causative CNVs in 9 myopathy cases by combining analysis of various mutation types.
• Unraveled complex genetic effects, including compound heterozygosity and compound diseases.
• Reported the first large intragenic deletion in the titin (TTN) gene associated with severe myopathy.
• Discovered a "double-trouble" genetic effect in a patient with TTN and dystrophin gene mutations.

Conclusions:

• CNV analysis is crucial for increasing the diagnostic rate in muscle diseases.
• Complex muscular dystrophy phenotypes can arise from diverse mutation types or combined genetic factors.