P.15.7 A founder mutation in the titin gene is a common cause of myofibrillar myopathy with early respiratory failure

Abstract

Titin gene (TTN) mutations have been described in 8 families with hereditary myopathy with early respiratory failure (HMERF) a rare condition with features resembling myofibrillar myopathy (MFM). In order to verify if TTN mutations could be a cause of MFM, especially in presence of early respiratory involvement, we carried out a clinical and genetic analysis of 127 undiagnosed patients with a clinical presentation compatible with MFM. Sanger sequencing for the TTN mutations previously described in patients with HMERF (p.C30071R and p.R32450W) was performed in all patients. We identified 5 families with the p.C30071R mutation (3.9% of study population) likely due to a British founder effect. Affected subjects showed phenotypic features similar to previously reported cases, and muscle pathology demonstrated diagnostic features of MFM. Two further families had novel variants in the 119th FN3 domain (p.P30091L and p.N30145K). Although still with uncertain pathogenicity, these new variants suggest that other TTN mutations in this domain may cause MFM. Our results indicate that mutations in TTN gene cause MFM and titinopathy is more common than previously thought. We suggest that HMERF due to mutations in the TTN gene be nosologically classified as MFM-titinopathy.