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Published on: November 29, 2024
Truncations of titin causing dilated cardiomyopathy
Daniel S Herman1, Lien Lam, Matthew R G Taylor
1Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
Insights
TTN gene mutations are a frequent cause of dilated cardiomyopathy, affecting about 25% of familial and 18% of sporadic cases. Genetic testing for TTN truncations can improve diagnosis and treatment for dilated cardiomyopathy patients.
Area of Science:
- Genetics
- Cardiology
- Molecular Biology
Background:
- Dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) are linked to numerous gene mutations.
- The TTN gene, encoding titin, is large and has been underexplored for cardiomyopathy-associated mutations.
Purpose of the Study:
- To investigate the role of TTN gene mutations in dilated cardiomyopathy and hypertrophic cardiomyopathy.
- To determine the frequency and clinical significance of TTN mutations in these cardiomyopathies.
Main Methods:
- Analyzed TTN gene in 312 DCM, 231 HCM patients, and 249 controls using next-generation or dideoxy sequencing.
- Evaluated deleterious variants for cosegregation in families and assessed clinical characteristics.
Main Results:
- Identified 72 unique TTN mutations affecting full-length titin.
- TTN mutations were significantly more frequent in DCM (27%) than in HCM (1%) or controls (3%).
- TTN mutations cosegregated with DCM in families with high penetrance after age 40; mutations were overrepresented in the titin A-band.
Conclusions:
- TTN truncating mutations are a common cause of DCM, found in approximately 25% of familial and 18% of sporadic cases.
- Integrating TTN mutation detection into genetic testing can enhance DCM diagnosis and facilitate earlier therapeutic intervention.
- Further research into the functional impact of TTN mutations will deepen the understanding of DCM pathophysiology.
Background:
Dilated cardiomyopathy and hypertrophic cardiomyopathy arise from mutations in many genes. TTN, the gene encoding the sarcomere protein titin, has been insufficiently analyzed for cardiomyopathy mutations because of its enormous size.
Methods:
We analyzed TTN in 312 subjects with dilated cardiomyopathy, 231 subjects with hypertrophic cardiomyopathy, and 249 controls by using next-generation or dideoxy sequencing. We evaluated deleterious variants for cosegregation in families and assessed clinical characteristics.
Results:
We identified 72 unique mutations (25 nonsense, 23 frameshift, 23 splicing, and 1 large tandem insertion) that altered full-length titin. Among subjects studied by means of next-generation sequencing, the frequency of TTN mutations was significantly higher among subjects with dilated cardiomyopathy (54 of 203 [27%]) than among subjects with hypertrophic cardiomyopathy (3 of 231 [1%], P=3×10(-16)) or controls (7 of 249 [3%], P=9×10(-14)). TTN mutations cosegregated with dilated cardiomyopathy in families (combined lod score, 11.1) with high (>95%) observed penetrance after the age of 40 years. Mutations associated with dilated cardiomyopathy were overrepresented in the titin A-band but were absent from the Z-disk and M-band regions of titin (P≤0.01 for all comparisons). Overall, the rates of cardiac outcomes were similar in subjects with and those without TTN mutations, but adverse events occurred earlier in male mutation carriers than in female carriers (P=4×10(-5)).
Conclusions:
TTN truncating mutations are a common cause of dilated cardiomyopathy, occurring in approximately 25% of familial cases of idiopathic dilated cardiomyopathy and in 18% of sporadic cases. 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. Defining the functional effects of TTN truncating mutations should improve our understanding of the pathophysiology of dilated cardiomyopathy. (Funded by the Howard Hughes Medical Institute and others.).
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