Dilated cardiomyopathy (DCM) is the most common form of non-ischemic cardiomyopathy.  While clinical evaluation identifies 30 to 50% of DCM patients as having a relative who is affected or likely to be affected, indicating a possible genetic cause, pathogenic mutations are found in only 20 to 30% of patients.  Therefore a large degree of uncertainty remains regarding the genetic causes of DCM.  TTN, the gene encoding titin, has been implicated in cardiomyopathy but has been incompletely studied, owing to technical challenges posed by the large size of its coding sequence (approximately 100 kb), translating into one of the largest human proteins, composed of approximately 33,000 amino acids.

In this study, using next generation sequencing technology, Herman et al., analysed TTN in 312 subjects with DCM, 231 subjects with hypertrophic cardiomyopathy (HCM), and 249 controls.  72 unique mutations that altered titin were found with significantly higher frequency among subjects with DCM (54 of 203 [27%]) than among subjects with HCM (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 with high (>95%) observed penetrance after the age of 40 years. Mutations associated with DCM were overrepresented in the A-band but were absent from the Z-disk and M-band regions of titin. 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:

Mutations in the protein titin are a common cause of dilated cardiomyopathy, occurring in approximately 25% of familial cases of idiopathic DCM. Not only does this study advance diagnostic tools for genetic screening of patients and families but it opens the door to a more fundamental understanding of the pathophysiology of DCM and the prospect of more targeted therapeutics.

• Herman DS, Lam L, Taylor MR, Wang L, Teekakirikul P, Christodoulou D, Conner L, DePalma SR, McDonough B, Sparks E, Teodorescu DL, Cirino AL, Banner NR, Pennell DJ, Graw S, Merlo M, Di Lenarda A, Sinagra G, Bos JM, Ackerman MJ, Mitchell RN, Murry CE, Lakdawala NK, Ho CY, Barton PJ, Cook SA, Mestroni L, Seidman JG and Seidman CE. Truncations of titin causing dilated cardiomyopathy.  N Engl J Med. 2012 Feb 16;366(7):619-28.