Novel Titin Gene Mutation Causing Autosomal Dominant Limb-Girdle Muscular Dystrophy.

We report a genotype-phenotype analysis of a family in which a titinopathy is transmitted in an autosomal dominant pattern. In this family, following neurological history and examination, electromyogram, and muscle biopsy, the diagnosis of limb-girdle muscular dystrophy with contractures was made in an affected mother and son. Genetic testing employing the whole exome was performed and revealed two variants in the TTN gene, c.712G>C, p. Glu238Gln and c.1397A>C, p.Gln466Arg, which segregated with the disease in the affected mother-son duo but not in an unaffected sibling. Although protein modeling suggests that the c.712G>C, p. Glu238Gln polymorphism is damaging, it has been reported in the Genome Aggregation Database which includes exome and genome sequence data of unrelated individuals sequenced as part of various disease-specific and population genetic studies. In contrast, the c.1397A>C, p.Gln466Arg variant is novel and has not been reported in any public genetic databases or our internal laboratory database. Protein modeling analysis indicates that p.Gln466Arg is damaging and we hypothesize that it is the disease-producing mutation resulting in muscular dystrophy. Our research report expands the spectrum of mutations causing titinopathy.