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Research paper
Titin founder mutation is a common cause of myofibrillar myopathy with early respiratory failure
  1. Gerald Pfeffer1,2,
  2. Rita Barresi3,
  3. Ian J Wilson1,
  4. Steven A Hardy1,
  5. Helen Griffin1,
  6. Judith Hudson1,
  7. Hannah R Elliott1,
  8. Aravind V Ramesh1,
  9. Aleksandar Radunovic4,
  10. John B Winer5,
  11. Sujit Vaidya4,
  12. Ashok Raman6,
  13. Mark Busby7,
  14. Maria E Farrugia8,
  15. Alec Ming6,
  16. Chris Everett4,
  17. Hedley C A Emsley9,
  18. Rita Horvath1,2,
  19. Volker Straub1,
  20. Kate Bushby1,
  21. Hanns Lochmüller1,
  22. Patrick F Chinnery1,2,
  23. Anna Sarkozy1
  1. 1Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle upon Tyne, UK
  2. 2Department of Neurology, Royal Victoria Infirmary, Newcastle upon Tyne, UK
  3. 3NCST Diagnostic and Advisory Service for Rare Neuromuscular Diseases, Muscle Immunoanalysis Unit, Newcastle upon Tyne, UK
  4. 4The Royal London Hospital, London, UK
  5. 5The Queen Elizabeth Hospital, Birmingham, UK
  6. 6Hull Royal Infirmary, Hull, UK
  7. 7St James's University Hospital, Leeds, UK
  8. 8Institute of Neurological Sciences, Glasgow, UK
  9. 9Department of Neurology, Royal Preston Hospital, Preston, UK
  1. Correspondence to Dr Anna Sarkozy, Institute of Genetic Medicine, International Centre for Life, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK; anna.sarkozy{at}


Objective Titin gene (TTN) mutations have been described in eight families with hereditary myopathy with early respiratory failure (HMERF). Some of the original patients had features resembling myofibrillar myopathy (MFM), arguing that TTN mutations could be a much more common cause of inherited muscle disease, especially in presence of early respiratory involvement.

Methods We studied 127 undiagnosed patients with clinical presentation compatible with MFM. Sanger sequencing for the two previously described TTN mutations in HMERF (p.C30071R in the 119th fibronectin-3 (FN3) domain, and p.R32450W in the kinase domain) was performed in all patients. Patients with mutations had detailed review of their clinical records, muscle MRI findings and muscle pathology.

Results We identified five new families with the p.C30071R mutation who were clinically similar to previously reported cases, and muscle pathology demonstrated diagnostic features of MFM. Two further families had novel variants in the 119th FN3 domain (p.P30091L and p.N30145K). No patients were identified with mutations at position p.32450.

Conclusions Mutations in TTN are a cause of MFM, and titinopathy is more common than previously thought. The finding of the p.C30071R mutation in 3.9% of our study population is likely due to a British founder effect. The occurrence of novel FN3 domain variants, although still of uncertain pathogenicity, suggests that other mutations in this domain may cause MFM, and that the disease is likely to be globally distributed. We suggest that HMERF due to mutations in the TTN gene be nosologically classified as MFM-titinopathy.


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