Hypertrophic Cardiomyopathy via the TNNC1 Gene

Hypertrophic cardiomyopathy (HCM) is a primary disease of the cardiac muscle characterized by idiopathic hypertrophy of the left ventricle, although hypertrophy of the right ventricle may occur occasionally (Fifer and Vlahakes Circulation 117:429-439, 2008). HCM is distinguished by an extensive clinical variability between individuals with regards to the age of onset, pattern and extent of hypertrophy, and prognosis. Symptoms include dyspnea, exercise intolerance, chest pain, palpitations, arrhythmia, atrial fibrillation, syncope, and sudden death (Maron et al. N Engl J Med 316:780-789, 1987). Additional features include left ventricular outflow tract obstruction, which is associated with increased risk for heart failure and cardiovascular death (Ommen et al. J Am Coll Cardiol 46:470-476, 2005). HCM affects 1 in 500 people worldwide (Maron et al. Circulation 92:785-789, 1995).

Dilated cardiomyopathy (DCM) is a heterogeneous disease of the heart muscle. It is characterized by dilatation of the left, right, or both ventricles; systolic dysfunction; and diminished myocardial contractility. Symptoms include arrhythmia, dyspnea, chest pain, palpitation, fainting, and congestive heart failure (Ikram et al. Br Heart J 57:521-527, 1987). Additional features may include woolly hair and myopathy (Moller et al. Eur J Hum Genet 17:1241-1249, 2009). Sudden death occurs in ~30% of patients with DCM (Tamburro and Wilber Am Heart J 124:1035-1045, 1992). Although symptoms of DCM usually begin in adulthood, an extensive clinical variability between individuals concerning the age of onset and extent of structural and functional abnormality has been documented. The prevalence of DCM has been estimated at ~1/2700 (Codd et al. Circulation 80:564-572, 1989).

HCM is a heterogeneous genetic disease that is inherited in an autosomal dominant manner. It is caused by variants in various genes, most of which encode sarcomeric proteins. Defects in fourteen genes, including the TNNC1 gene (Cirino and Ho GeneReviews, 2011; Hoffmann et al. Hum Mutat 17:524, 2001), account for approximately 60% of all HCM cases. Variants were identified in both familial and sporadic cases, with similar distribution. Variants identified in sporadic cases were either nonpenetrant in family members or occurred de novo (Richard et al. Circulation 107:2227-2232, 2003). Some patients with severe phenotype were shown to have more than one variant, either in two different genes or in the same gene (Richard et al. 2003). To date, six different TNNC1 causative variants were reported in patients with HCM. These include five missense variants and one small insertion. In addition to HCM, five heterozygous TNNC1 variants were found in patients with dilated cardiomyopathy (DCM) (Mogensen et al. J Am Coll Cardiol 44:2033-2040, 2004). The TNNC1 gene encodes cardiac troponin C, a sarcomeric protein that is involved in actin-myosin interactions.

Variants in TNNC1 are found in less than 1% of patients with HCM and DCM (Hershberger et al. Circ Heart Fail 2:253-261, 2009).

This test provides full coverage of all coding exons of the TNNC1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).