Hypertrophic Cardiomyopathy (HCM) is a common primary cardiac disorder defined 
by a hypertrophied left ventricle, is one of the main causes of sudden death in 
young athletes, and has been associated with mutations in most sarcomeric 
proteins (tropomyosin, troponin T and I, and actin, etc.). Many of these 
mutations appear to affect the functional properties of cardiac troponin C 
(cTnC), i.e., by increasing the Ca(2+)-sensitivity of contraction, a hallmark of 
HCM, yet surprisingly, prior to this report, cTnC had not been classified as a 
HCM-susceptibility gene. In this study, we show that mutations occurring in the 
human cTnC (HcTnC) gene (TNNC1) have the same prevalence (~0.4%) as well 
established HCM-susceptibility genes that encode other sarcomeric proteins. 
Comprehensive open reading frame/splice site mutation analysis of TNNC1 
performed on 1025 unrelated HCM patients enrolled over the last 10 years 
revealed novel missense mutations in TNNC1: A8V, C84Y, E134D, and D145E. 
Functional studies with these recombinant HcTnC HCM mutations showed increased 
Ca(2+) sensitivity of force development (A8V, C84Y and D145E) and force recovery 
(A8V and D145E). These results are consistent with the HCM functional phenotypes 
seen with other sarcomeric-HCM mutations (E134D showed no changes in these 
parameters). This is the largest cohort analysis of TNNC1 in HCM that details 
the discovery of at least three novel HCM-associated mutations and more strongly 
links TNNC1 to HCM along with functional evidence that supports a central role 
for its involvement in the disease. This study may help to further define TNNC1 
as an HCM-susceptibility gene, a classification that has already been 
established for the other members of the troponin complex.