title: Titin founder mutation is a common cause of myofibrillar myopathy with early respiratory failure.
abstract: 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.
authors.affiliation: Institute of Genetic Medicine, International Centre for Life, Newcastle University, , Newcastle upon Tyne, UK.
authors.forename: Gerald
authors.initials: G
authors.lastname: Pfeffer
authors.forename: Rita
authors.initials: R
authors.lastname: Barresi
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Wilson
authors.forename: Steven A
authors.initials: SA
authors.lastname: Hardy
authors.forename: Helen
authors.initials: H
authors.lastname: Griffin
authors.forename: Judith
authors.initials: J
authors.lastname: Hudson
authors.forename: Hannah R
authors.initials: HR
authors.lastname: Elliott
authors.forename: Aravind V
authors.initials: AV
authors.lastname: Ramesh
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Radunovic
authors.forename: John B
authors.initials: JB
authors.lastname: Winer
authors.forename: Sujit
authors.initials: S
authors.lastname: Vaidya
authors.forename: Ashok
authors.initials: A
authors.lastname: Raman
authors.forename: Mark
authors.initials: M
authors.lastname: Busby
authors.forename: Maria E
authors.initials: ME
authors.lastname: Farrugia
authors.forename: Alec
authors.initials: A
authors.lastname: Ming
authors.forename: Chris
authors.initials: C
authors.lastname: Everett
authors.forename: Hedley C A
authors.initials: HC
authors.lastname: Emsley
authors.forename: Rita
authors.initials: R
authors.lastname: Horvath
authors.forename: Volker
authors.initials: V
authors.lastname: Straub
authors.forename: Kate
authors.initials: K
authors.lastname: Bushby
authors.forename: Hanns
authors.initials: H
authors.lastname: Lochmüller
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Chinnery
authors.forename: Anna
authors.initials: A
authors.lastname: Sarkozy
mesh_terms: D000328:Adult; D000368:Aged; D064211:Connectin / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D030342:Genetic Diseases, Inborn / Q000235:genetics* / Q000473:pathology; D006239:Haplotypes; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000473:pathology; D009135:Muscular Diseases / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D010375:Pedigree; D016133:Polymerase Chain Reaction; D012131:Respiratory Insufficiency / Q000235:genetics* / Q000473:pathology
chemical_list: D064211:Connectin; C577285:TTN protein, human
keywords: GENETICS; MUSCULAR DYSTROPHY; MYOPATHY; NEUROPATHOLOGY, MUSCLE; RESPIRATORY MEDICINE