Truncations of Titin Causing Dilated Cardiomyopathy

Study Questions:

How frequent are titin (TTN) mutations in patients with dilated cardiomyopathy (DCM)?

Methods:

The gene for TTN was analyzed in 312 subjects with DCM, 231 subjects with HCM, and 249 controls using next-generation or dideoxy sequencing. Gene variants and clinical phenotypes were analyzed for cosegregation in families.

Results:

A total of 72 unique mutations (25 nonsense, 23 frameshift, 23 splicing, and 1 large tandem insertion) that altered full-length TTN were identified. The frequency of TTN mutations was significantly higher among subjects with DCM (27%) compared to subjects with HCM (1%, P=3×10−16) or controls (3%, P=9×10−14). TTN mutations cosegregated with DCM in families (lod score, 11.1) with high (>95%) penetrance after the age of 40 years. The rates of cardiac outcomes were similar between subjects with and without TTN mutations, but adverse events occurred earlier in male mutation carriers than in female carriers (P=4×10−5).

Conclusions:

The authors concluded that TTN truncating mutations are a common cause of DCM, occurring in approximately 25% of familial cases of idiopathic DCM and in 18% of sporadic cases. Incorporation of sequencing approaches that detect TTN truncations into genetic testing for DCM should increase test sensitivity, thereby allowing earlier diagnosis and therapeutic intervention for many patients with DCM.

Perspective:

Titin is a giant sarcomere protein with many potential functions, including regulation of myocyte elasticity and contractile force. Because TTN is encoded by a giant gene, sequencing analysis for TTN mutations in patients with cardiomyopathies has been incomplete. Using modern sequencing methods in a large affected patient population, these investigators have now established that TTN truncating mutations are the most common genetic cause of DCM. In addition to providing biological insight into the pathophysiology of DCM, these findings also have important implications for mutation analysis in patients with DCM and family screening.

Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure

Keywords: Mutation, Frameshift Mutation, Lod Score, Cardiomyopathies, Heart Failure, Genetic Testing, DNA Mutational Analysis, Connectin, Sarcomeres, Penetrance, Cardiomyopathy, Dilated, Elasticity


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