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Open Access Research article

Exome sequencing identifies titin mutations causing hereditary myopathy with early respiratory failure (HMERF) in families of diverse ethnic origins

Camilo Toro1, Montse Olivé2, Marinos C Dalakas3, Kumaraswami Sivakumar4, Juan M Bilbao5, Felix Tyndel6, Noemí Vidal7, Eva Farrero8, Nyamkhishig Sambuughin9 and Lev G Goldfarb10*

Author affiliations

1 Undiagnosed Diseases Program, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

2 Institute of Neuropathology, Department of Pathology and Neuromuscular Unit, Department of Neurology, IDIBELL-Hospital Universitari de Bellvitge and Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain

3 University of Athens Medical School, 75 Mikras Asias, Athens, Greece

4 Barrow Neurological Institute, Phoenix, AZ, USA

5 Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada

6 Toronto Western Hospital, University of Toronto, Toronto, ON, Canada

7 Institute of Neuropathology, Department of Pathology, IDIBELL-Hospital Universitari de Bellvitge, Barcelona, Spain

8 Pneumology Service, IDIBELL-Hospital Universitari de Bellvitge, Barcelona, Spain

9 Uniformed Services University, Bethesda, MD, USA

10 National Institute of Neurological Disorders and Stroke, National Institutes of Health, Room 4S06, 5625 Fishers Lane, Bethesda, MD MSC 9404, USA

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Citation and License

BMC Neurology 2013, 13:29  doi:10.1186/1471-2377-13-29

Published: 20 March 2013

Abstract

Background

Hereditary myopathy with early respiratory failure (HMERF) was described in several North European families and recently linked to a titin gene (TTN) mutation. We independently studied HMERF-like diseases with the purpose to identify the cause, refine diagnostic criteria, and estimate the frequency of this disease among myopathy patients of various ethnic origins.

Methods

Whole exome sequencing analysis was carried out in a large U.S. family that included seven members suffering from skeletal muscle weakness and respiratory failure. Subsequent mutation screening was performed in further 45 unrelated probands with similar phenotypes. Studies included muscle strength evaluation, nerve conduction studies and concentric needle EMG, respiratory function test, cardiologic examination, and muscle biopsy.

Results

A novel TTN p.Gly30150Asp mutation was identified in the highly conserved A-band of titin that co-segregated with the disease in the U.S. family. Screening of 45 probands initially diagnosed as myofibrillar myopathy (MFM) but excluded based on molecular screening for the known MFM genes led to the identification of a previously reported TTN p.Cys30071Arg mutation in one patient. This same mutation was also identified in a patient with suspected HMERF. The p.Gly30150Asp and p.Cys30071Arg mutations are localized to a side chain of fibronectin type III element A150 of the 10th C-zone super-repeat of titin.

Conclusions

Missense mutations in TTN are the cause of HMERF in families of diverse origins. A comparison of phenotypic features of HMERF caused by the three known TTN mutations in various populations allowed to emphasize distinct clinical/pathological features that can serve as the basis for diagnosis. The newly identified p.Gly30150Asp and the p.Cys30071Arg mutation are localized to a side chain of fibronectin type III element A150 of the 10th C-zone super-repeat of titin.

Keywords:
Myopathy; Respiratory failure; HMERF; Titin; Titin A-band mutation; Fibronectin type III