NEJM：扩张型心肌病与TTN基因突变有关

Daniel S. Herman, Ph.D., Lien Lam, Ph.D., Matthew R.G. Taylor, M.D., Ph.D., Libin Wang, M.D., Ph.D., Polakit Teekakirikul, M.D., Danos Christodoulou, B.S., Lauren Conner, B.S., Steven R. DePalma, Ph.D., Barbara McDonough, R.N., Elizabeth Sparks, R.N.P., Debbie Lin Teodorescu, M.A., Allison L. Cirino, C.G.C., Nicholas R. Banner, F.R.C.P., Dudley J. Pennell, M.D., Sharon Graw, Ph.D., Marco Merlo, M.D., Andrea Di Lenarda, M.D., Gianfranco Sinagra, M.D., J. Martijn Bos, M.D., Ph.D., Michael J. Ackerman, M.D., Ph.D., Richard N. Mitchell, M.D., Ph.D., Charles E. Murry, M.D., Ph.D., Neal K. Lakdawala, M.D., Carolyn Y. Ho, M.D., Paul J.R. Barton, Ph.D., Stuart A. Cook, M.D., Luisa Mestroni, M.D., J.G. Seidman, Ph.D., and Christine E. Seidman, M.D.

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.)

Supported by grants from the Howard Hughes Medical Institute (to Dr. C.E. Seidman); the National Institutes of Health (to Drs. Herman, Taylor, Graw, Ackerman, Mitchell, Murry, Ho, Mestroni, and J.G. Seidman); the Leducq Foundation (to Drs. Cook, J.G. Seidman, and C.E. Seidman); the American Heart Association and the Muscular Dystrophy Association (to Drs. Taylor and Mestroni); the U.K. National Institute for Health Research Cardiovascular Biomedical Research Unit (Royal Brompton and Harefield National Health Service Foundation Trust and Imperial College), the British Heart Foundation, and the Medical Research Council U.K. (to Drs. Banner, Pennell, Cook, and Barton); and the J. Ira and Nicki Harris Family Research Award (to Dr. Ho). Sequencing in subjects with dilated cardiomyopathy in group C was funded by a contract from the National Heart, Lung, and Blood Institute (N01-HV-48194).