Myotilin gene duplication causing late-onset myotilinopathy

Area of Science:

• Genetics
• Neuromuscular Disorders
• Molecular Biology

Background:

• Myotilinopathy is a rare inherited muscle disease within the myofibrillar myopathies group.
• Characterized by Z disk alterations, protein aggregation, and muscle degeneration.
• Typically caused by dominant MYOT gene mutations, with recurrent variants reported.

Purpose of the Study:

• To investigate the genetic basis of late-onset dominant proximodistal myopathy with muscle hypertrophy in a family.
• To expand the understanding of the molecular spectrum of myotilinopathy.

Main Methods:

• Comprehensive analysis including clinical, radiological, pathological, and molecular evaluations.
• Utilized long-read sequencing for detailed genetic investigation.
• Focused on a family presenting with late-onset myopathy and hypertrophy.

Main Results:

• Identified a duplication of the entire MYOT gene as the causative genetic alteration.
• The identified duplication correlated with typical clinical and pathological features of late-onset myotilinopathy.

Conclusions:

• The study expands the known genetic causes of myotilinopathy.
• Highlights the utility of long-read sequencing for diagnosing genetic disorders involving structural variants like duplications.
• Recommends considering myotilinopathy and other distal myopathies in differential diagnoses for late-onset distal muscle weakness.