TTN Mutation Detection Aids Cardiomyopathy Diagnosis

(HealthDay News) – Adding sequencing approaches that detect genetic mutations in the TTN gene, which codes for the sarcomere protein titin, would enable earlier diagnosis and improved treatment for patients with dilated cardiomyopathy, according to a study published in the Feb. 16 issue of the New England Journal of Medicine.

Daniel S. Herman, PhD, of Harvard Medical School in Boston, and colleagues used next-generation or dideoxy sequencing to analyze TTN in 312 individuals with dilated cardiomyopathy, 231 with hypertrophic cardiomyopathy, and 249 controls. Deleterious variants for cosegregation in families were evaluated, and clinical characteristics were assessed.

The researchers identified 72 unique mutations, including 25 nonsense mutations, 23 frameshift, 23 splicing, and one large tandem insertion, that altered full-length titin. Based on next-generation sequencing, the frequency of TTN mutations was significantly higher among individuals with dilated cardiomyopathy (27%) than among subjects with hypertrophic cardiomyopathy (1%) or controls (3%). In families with high (>95%) observed penetrance after the age of 40 years, TTN mutations cosegregated with dilated cardiomyopathy. Mutations associated with dilated cardiomyopathy were absent from the titin Z-disc and M-band and were overrepresented in the A-band. While the rates of cardiac outcomes were similar in subjects regardless of TTN mutations, adverse events occurred earlier in male than in female mutation carriers.

“Incorporation of sequencing approaches that detect TTN truncations into genetic testing for dilated cardiomyopathy should substantially increase test sensitivity, thereby allowing earlier diagnosis and therapeutic intervention for many patients with dilated cardiomyopathy,” the authors write.

Several authors disclosed financial relationships with pharmaceutical and biotechnology companies.

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