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Reply: Hereditary myopathy with early respiratory failure is caused by mutations in the titin FN3 119 domain

Gerald Pfeffer, Patrick F. Chinnery
DOI: http://dx.doi.org/10.1093/brain/awu034 e280 First published online: 27 February 2014

Sir, The response by Lange et al. (2014) provides important confirmatory information. The coincidence of the FN 119 domain mutation (p.P30091L) with the kinase domain variant (p.R32450W or R279W) in all patients previously reported by Lange et al. (2005) confirms speculation (Hedberg et al., 2013; Pfeffer et al., 2013) that the HMERF in the original family was primarily a result of the p.P30091L FN 119 mutation, and not to the kinase domain variant (p.R32450W or R279W). The kinase domain variant (p.R32450W or R279W) was originally reported to be the cause of HMERF by Lange et al. (2005), but has subsequently been reported in healthy control subjects. On the other hand, the p.P30091L FN 119 mutation has been reported repeatedly and exclusively in HMERF families.

Lange et al. (2014) suggest that we contradict ourselves regarding the pathogenicity of the p.P30091L variant, citing out of context (and out of chronological order) our report in which we considered p.P30091L as a possible neutral variant (Pfeffer et al., 2014). However, we had also …