Widening the spectrum of TTN myopathies: identification of a novel variant causing a variable mild myopathy with multiple contractures

The gene Titin (TTN) encodes the largest sarcomeric protein residing within the striated muscle cells. The protein is considered to include many domains: the N-terminal that incorporates the Z- line, the I-band, and the A-band as well as the M-line at the C-terminal. TTN mutations are known to cause a wide spectrum of disorders including tibial muscular dystrophy (TMD), limb–girdle muscular dystrophy type 2J (LGMD2J), and autosomal recessive early onset myopathy with fatal cardiomyopathy (EOMFC). Next-generation sequencing allows a large number of gene exons to be sequenced at once providing the opportunity to easily analyze giant genes such as TTN. Rare missense variants that are considered to be pathogenic represent a small percentage of hundreds of rare TTN missense variants that are identified; therefore, missense mutations are considered to be frequent in TTN and usually benign. Today, clinical diagnostic testing is able to analyze over 150 myopathy genes, including TTN; however, the size and the scale of variation in this gene are of great clinical challenge when it comes to identifying disease-causing mutations. We recruited a large Iranian family presenting with a dominantly inherited variable myopathy with multiple contractures. Whole exome sequencing performed on four affected individuals from the family uncovered only one shared novel variant in TTN. The variant: c.36877A>T causes a substitution of Isoleucine to Phenylalanine at the position 12293 within the Ig-like 82 domain of the I-band, which is largely composed of Ig-like domains and is believed to be responsible for the molecule's extensibility and elasticity. This variant has never been reported in public databases and is predicted to be disease causing by the MutationTaster, SIFT, Polyphen2 and I-Mutant software. The identification of a rare TTN missense variant co-segregating with a variable myopathy with multiple contractures phenotype suggests the importance of TTN as a disease-causing gene in milder myopathy phenotypes.

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