Hypertrophic Cardiomyopathy Panel

Hypertrophic cardiomyopathy (HCM) is characterized by hypertrophy of the left ventricle; however, hypertrophy of the right ventricle may also occur (Gersh et al. 2011. PubMed ID: 22068435). Symptoms are extremely variable and range from asymptomatic to shortness of breath (dyspnea), exercise intolerance, chest pain, palpitations, arrhythmia, syncope, heart failure, and sudden death (Maron et al. 1987. PubMed ID: 3547130). HCM can also present with left ventricular outflow tract obstructions, which are associated with increased risk for heart failure (Ommen et al. 2005. PubMed ID: 16053960). HCM is one of the most common inherited cardiovascular diseases with a prevalence of 1 in every 500 individuals in the general population (Maron et al. 1995. PubMed ID: 7641357). Age of onset is highly variable and can range from infancy to adulthood. Penetrance is incomplete and age dependent. Onset and severity cannot be predicted as there is variable expressivity, even within families.

Advantages of testing include: identification of asymptomatic individuals at risk of carrying pathogenic variants and in the prognosis of patients. Positive cases have poorer outcomes compared to negative cases (Olivotto et al. 2008. PubMed ID: 18533079).

HCM can also present as part of a syndrome, as HCM is a common feature in patients with Noonan syndrome/RASopathies, Pompe, and Fabry disease. Although onset in these syndromes is typically in infancy, a small percentage of adults with isolated HCM have pathogenic variants in genes associated with Noonan syndrome/RASopathies (Ceyhan-Birsoy et al. 2018. PubMed ID: 29696744). Fabry disease patients often have renal and cardiac features with onset of HCM in early to late adulthood (Sachdev et al. 2002. PubMed ID: 11914245; Nakao et al. 2003. PubMed ID: 12911529).

The majority of HCM-related genes are inherited in an autosomal dominant manner. However, other modes of inheritance have been described, such as autosomal recessive (ALPK3, GAA, MYPN); X-linked recessive (FHL1 and GLA), and X-linked dominant (LAMP2). The DES, LZTR1, MYPN, and TCAP genes are associated with autosomal dominant and recessive cardiac disorders.

HCM is considered a disorder of the sarcomere, as 30-60% of individuals with HCM have pathogenic variants in genes encoding components of the sarcomere, which is responsible for the contraction of heart muscle (Van Driest et al. 2005. PubMed ID: 15819282; Bos et al. 2014. PubMed ID: 24793961). Pathogenic variants in MYBPC3 and MYH7 are the most common cause of inherited HCM (Van Driest et al. 2005. PubMed ID: 15819282; Bos et al. 2014. PubMed ID: 24793961). The spectrum of pathogenic variants in HCM includes missense, nonsense, frameshift, splicing, and copy number variants. Loss-of-function variants in the MYBPC3 gene are a known cause of disease; however, in most other genes they are of uncertain significance.

The majority of pathogenic variants are thought to be familial; however, de novo events have been reported rarely (Döhlemann et al. 2000. PubMed ID: 10957787).

Copy number variation appears to be a rare cause, as pathogenic deletions were found in 1-2% of patients with HCM (Mademont-Soler et al. 2017. PubMed ID: 28771489; Mates et al. 2018. PubMed ID: 29511324).

See individual gene summaries for more information about molecular biology of gene products and spectra of pathogenic variants.

This test will detect pathogenic variants in 30-60% of hypertrophic cardiomyopathy patients (Van Driest et al. 2005. PubMed ID: 15819282; Bos et al. 2014. PubMed ID: 24793961). A number of factors (age of onset, family history, septal shape, ventricular wall thickness, hypertension) can significantly impact the sensitivity, which ranged from 6% (hypertension only) to 80% (all clinical markers) (Bos et al. 2014. PubMed ID: 24793961).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 98.5% coverage of all coding exons of the genes 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 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).