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

Camilo Toro,Noemí Vidal,Juan M Bilbao,Felix Tyndel,Kumaraswami Sivakumar,Eva Farrero,Lev G Goldfarb,Montse Olivé,Marinos C Dalakas,Nyamkhishig Sambuughin

doi:10.1186/1471-2377-13-29

Abstract

BackgroundHereditary 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.MethodsWhole 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.ResultsA 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.ConclusionsMissense 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.

Highlights

Hereditary myopathy with early respiratory failure (HMERF) was described in several North European families and recently linked to a titin gene (TTN) mutation
Hereditary myopathy with early respiratory failure (HMERF) known as Edström myopathy is a disorder manifesting with predominantly proximal muscle weakness of the lower and upper extremities with respiratory insufficiency and involvement of neck flexors early in the disease course [1]
Clinical and laboratory evaluation We studied in detail 7 patients from three unrelated families reffered to as families A, B, and C suffering from skeletal myopathy and respiratory failure

Summary

Introduction

Hereditary myopathy with early respiratory failure (HMERF) was described in several North European families and recently linked to a titin gene (TTN) mutation. The first TTN mutation causing HMERF has been identified by Lange and colleagues [5] in Swedish families originally described by Edström et al [1]. This mutation was defined as p.Arg279Trp by using residue numbering according to the crystal structure of the titin kinase domain [6]. HMERF in several newer North European families have been associated with a g.274375T>C: p.Cys30071Arg mutation in the A-band of titin [7,8]

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