Genetic Testing Program for Hypertrophic Cardiomyopathy (HCM)

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.

HCM can also present as part of a syndrome, as HCM is a common feature in patients with Noonan syndrome/ RASopathies, Pompe disease, 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). Individuals with Fabry disease 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, and 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 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.

1. Patient is between the age of 18 - 65 years at the time of enrollment.
2. Patient has a history of nonobstructive HCM.
3. Patient has an implantable cardioverter-defibrillator (ICD).

1. Determine if the individual meets eligibility criteria and discuss the test. One no-charge pre-test genetic counseling appointment with a third-party service (provided by Genome Medical) is available to patients through this sponsored testing program.
2. Order the test using the test requisition form.
3. Collect a blood, saliva, or buccal specimen in the collection tube. For information on ordering specimen kits, see Specimen Collection and Shipping section.
4. The genetic test will be processed at PreventionGenetics and the results will be sent to the ordering healthcare provider about 18 days after the lab receives the specimens and all appropriately completed paperwork.
5. The ordering healthcare provider will discuss the results with the patient and/or caregiver. One no-charge post-test genetic counseling appointment with a third-party service (provided by Genome Medical) is available to patients through this sponsored testing program.

SPECIMEN REQUIREMENTS

Whole Blood

Collect 3 ml - 5 ml of whole blood in EDTA (purple top tube) or ACD (yellow top tube), minimum 1 ml for small infants. Specimens may be refrigerated and/or shipped at room temperature.

Saliva

Oragene™ or GeneFiX™ Saliva Collection kit used according to manufacturer instructions. DNA from saliva specimens is invariably contaminated with microbial and food DNA, which can impact specimen quality and may result in delayed testing and/or the need for a second specimen. Specimens may be shipped at room temperature.

OCD-100 Buccal Swab (Preferred)

OCD-100 Buccal Swab used according to manufacturer instructions. Specimens may be shipped at room temperature.

SHIPPING AND HANDLING INSTRUCTIONS

Label all specimen containers with the patient's name, date of birth, and/or ID number. At least two identifiers should be listed on specimen containers. Specimen deliveries are accepted Monday-Saturday for all specimen types. Holiday schedules will be posted on our website at least one week prior to major holidays.