Exome sequencing identifies a novel TTN mutation in a family with hereditary myopathy with early respiratory failure

Area of Science:

• Genetics
• Molecular Biology
• Neurology

Background:

• Myofibrillar myopathy (MFM) encompasses chronic muscle disorders with myofibril dissolution, but its genetic causes remain largely unknown.
• A previously reported Japanese family exhibited dominantly inherited cytoplasmic body myopathy, now classified under MFM, with late-onset distal weakness and early respiratory failure.

Purpose of the Study:

• To identify the genetic basis of myofibrillar myopathy in a Japanese family with a history of dominant inheritance.
• To investigate the potential role of the TTN gene in the pathogenesis of MFM and related neuromuscular disorders.

Main Methods:

• Linkage analysis was performed on affected family members.
• Exome sequencing was utilized to identify causative mutations.
• Mutation screening of the TTN gene was conducted.

Main Results:

• A novel mutation, c.90263G>T, was identified in the TTN gene (NM_001256850) in the studied family.
• The identified mutation and previously reported TTN mutations associated with hereditary myopathy with early respiratory failure (HMERF) are located in the A-band domain of titin.
• Clinical presentation of the patients was consistent with HMERF.

Conclusions:

• Mutations in the TTN gene, particularly in the A-band domain, are strongly associated with hereditary myopathy with early respiratory failure (HMERF).
• The TTN gene should be considered in the genetic analysis of patients with myofibrillar myopathies, especially those presenting with early respiratory failure.
• Focused analysis of the large TTN gene may reveal additional mutations in MFM patients.