Hypertrophic Cardiomyopathy and Related Disorders via the ACTC1 Gene

Hypertrophic cardiomyopathy (HCM) is a disease of the cardiac muscle characterized by idiopathic hypertrophy of the left ventricle without predisposing conditions, such as aortic stenosis or hypertension (Cirino et al. GeneReviews). Hypertrophy of the right ventricle may also occur occasionally (Fifer and Vlahakes. Circulation 117:429-439, 2008). HCM is distinguished by extensive clinical variability with regards to the age of onset, pattern and extent of hypertrophy, and prognosis, even within individuals of the same family. Symptoms include dyspnea, exercise intolerance, chest pain, palpitations, arrhythmia, atrial fibrillation, presyncope, 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 if left untreated (Ommen et al. J Am Coll Cardiol 46:470-476, 2005; Agarwal et al. Am Coll Cardiol 55:823-834, 2010). HCM is most often diagnosed with 2D echocardiography, but can also be diagnosed by the presence of myocyte disarray upon histological examination and through genetic testing. HCM affects 1 in 500 people worldwide (Maron et al. Circulation 92:785-789, 1995).

Idiopathic Dilated cardiomyopathy (DCM) is a heterogeneous disease of the cardiac muscle. It is characterized by enlargement of the left ventricle, systolic dysfunction, and diminished myocardial contractility (Hershberger et al. GeneReviews). Symptoms include arrhythmia, dyspnea, chest pain, palpitation, fainting, and congestive heart failure (Ikram et al. Br Heart J 57:521-527, 1987). 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, penetrance, and extent of structural and functional abnormalities has been documented. Familial DCM is diagnosed based on family history and genetic testing. The prevalence of DCM has been estimated at ~1 in 2700 individuals (Codd et al. Circulation 80:564-572, 1989).

Familial HCM is inherited in an autosomal dominant manner caused by mutations in genes that encode different components of the sarcomere. Defects in fourteen genes, including ACTC1 (Mogensen et al. J Clin Invest 103:R39-43, 1999), account for approximately 60% of all HCM cases. Mutations have been identified in both familial and sporadic cases, with similar distribution. Mutations identified in sporadic cases were either nonpenetrant in family members or arose de novo. Most documented causative mutations in ACTC1 in patients with HCM are missense mutations. In addition to HCM, ACTC1 mutations have been implicated in dilated cardiomyopathy (DCM) (Olson et al. Science 280:750-752, 1998), left ventricular noncompaction (LVNC) (Monserrat et al. Europ Heart J 28:1953-1961, 2007) childhood restrictive cardiomyopathy (RCM) (Kaski et al. Heart 94:1478-1484, 2008) and in patients with atrial septal defect (ASD5) (Matsson et al. Hum Mol Genet 17:256-265, 2008).

ACTC1 pathogenic mutations are rare. Perhaps 1% of HCM patients with known causative mutations have mutations in ACTC1 (Hershberger et al. Circ Heart Fail 2:253-261, 2009). Less than 1% of patients with ASD5 have mutations in ACTC1 (Matsson et al. Hum Molec Genet 17:256-265, 2008).

This test provides full coverage of all coding exons of the ACTC1 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).