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Titin founder mutation is a common cause of myofibrillar myopathy with early respiratory failure

Lookup NU author(s): Dr Gerald Pfeffer, Dr Rita Barresi, Dr Ian Wilson, Dr Steven Hardy, Dr Helen GriffinORCiD, Dr Hannah Elliott, Professor Rita HorvathORCiD, Professor Volker StraubORCiD, Emerita Professor Katherine Bushby, Professor Hanns Lochmuller, Professor Patrick Chinnery, Dr Anna Sarkozy


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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.

Publication metadata

Author(s): Pfeffer G, Barresi R, Wilson IJ, Hardy SA, Griffin H, Hudson J, Elliott HR, Ramesh AV, Radunovic A, Winer JB, Vaidya S, Raman A, Busby M, Farrugia ME, Ming A, Everett C, Emsley HCA, Horvath R, Straub V, Bushby K, Lochmuller H, Chinnery PF, Sarkozy A

Publication type: Article

Publication status: Published

Journal: Journal of Neurology, Neurosurgery & Psychiatry

Year: 2014

Volume: 85

Issue: 3

Pages: 331-338

Print publication date: 13/03/2013

ISSN (print): 0022-3050

ISSN (electronic): 1468-330X

Publisher: BMJ Publishing Group


DOI: 10.1136/jnnp-2012-304728


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Funder referenceFunder name
Association Francaise contre les Myopathies
Canadian Institutes of Health Research
Medical Research Council (UK) Centre for Translational Muscle Disease research
National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre based at Newcastle upon Tyne Hospitals NHS Foundation Trust
National Specialised Commissioning Team (NSCT)
Newcastle University
096919Z/11/ZWellcome Trust Centre for Mitochondrial Research