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A new disease allele for the p.C30071R mutation in titin causing hereditary myopathy with early respiratory failure

Lookup NU author(s): Dr Gerald Pfeffer, Professor Patrick Chinnery



This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


Hereditary myopathy with early respiratory failure is an autosomal dominant myopathy caused by mutations in the 119th fibronectin-3 domain of titin. To date all reported patients with the most common mutation in this domain (p.C30071R) appear to share ancestral disease alleles. We undertook this study of two families with the p.C30071R mutation to determine whether they share the same haplotype as previously reported British families or whether the mutation arose as a de novo event. We sequenced the 119th fibronectin-3 domain in these two probands and flanking polymorphisms associated with the British haplotype in hereditary myopathy with early respiratory failure. A family of Indian descent had a haplotype that was not compatible with the British shared haplotype. Cloning of the 119th fibronectin-3 domain in this patient demonstrated polymorphisms rs191484894 and novel noncoding variant c.90225C>T on the same allele as the mutation, which is distinct from previously reported British families. This proves that the p.C30071R mutation itself (rather than the haplotype containing this mutation) causes hereditary myopathy with early respiratory failure and suggests its independent origin in different ethnic groups. (C) 2013 The Authors. Published by Elsevier B.V. All rights reserved.

Publication metadata

Author(s): Pfeffer G, Sambuughin N, Olive M, Tyndel F, Toro C, Goldfarb LG, Chinnery PF

Publication type: Article

Publication status: Published

Journal: Neuromuscular Disorders

Year: 2014

Volume: 24

Issue: 3

Pages: 241-244

Print publication date: 01/03/2014

Online publication date: 11/12/2013

Acceptance date: 02/12/2013

Date deposited: 09/06/2014

ISSN (print): 0960-8966

ISSN (electronic): 1873-2364

Publisher: Elsevier Ltd


DOI: 10.1016/j.nmd.2013.12.001


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