New disease allele and de novo mutation indicate mutational vulnerability of titin exon 343 in hereditary myopathy with early respiratory failure.

We report two patients of Chinese ancestry with hereditary myopathy with early respiratory failure, one sporadic with atypical onset as rigid spine syndrome, the other familial with 10 years' history of hyperCKemia. Muscle biopsy was either nonspecific or typical with cytoplasmic bodies and rimmed vacuoles. Despite the phenotypic variety, both patients showed fatty infiltration of semitendinosus on muscle magnetic resonance imaging. Genetic analysis of case 1 disclosed de novo heterozygous missense mutations in the 119th fibronectin 3 domain of titin [c.90272C>T, p.P30091L]. Haplotype analysis of case 2 revealed a heterozygous missense mutation [c.90211T>C, p.C30071R] on a new disease allele incompatible with the British common haplotype. These findings suggest that hereditary myopathy with early respiratory failure is a worldwide distributed disorder and indicate the mutational vulnerability of TTN exon 343 in which de novo mutations could occur on different haplotype backgrounds.