Diagnostics

Learn how our advanced genetic tests are revolutionizing health

Hypertrophic Cardiomyopathy Panel

The Hypertrophic Cardiomyopathy Panel is a comprehensive next-generation sequencing (NGS) panel that can be used to confirm a clinical diagnosis of hypertrophic cardiomyopathy or identify at-risk individuals. Hypertrophic cardiomyopathy is characterized by thickening of the heart musclewhich can cause obstruction of blood flow out of the left ventricleor decreased efficiency in pumping blood. Symptoms of the condition  mayinclude chest pain, shortness of breath, lightheadedness, and fainting, although many individuals will not have any symptoms of the condition at all. Hypertrophic cardiomyopathy can lead to abnormal heart rhythms or heart failure in some individuals.  The condition increases a person’s risk for sudden cardiac death, even in the absence of other symptoms.

Prevalence

Hypertrophic cardiomyopathy affects approximately 1 in 500 individuals, with some estimates as high as 1 in 200 (Semsarian et al, 2015).

Included disorders

This panel includes genes related to primary hypertrophic cardiomyopathy as well as genes associated with disorders that include hypertrophic cardiomyopathy as a feature. These disorders include:

  • Danon disease
  • Fabry disease
  • Myofibrillar myopathy
  • Timothy syndrome
  • Transthyretin (TTR) amyloidosis
  • Wolff-Parkinson-White syndrome
  • Other disorders

Inheritance and Penetrance

Hypertrophic cardiomyopathy is typically inherited in an autosomal dominant fashion, meaning that an affected individual has a 50% chance of passing on the condition, although some forms are inherited in a recessive, and X-linked manner. Hypertrophic cardiomyopathy typically exhibits reduced and age-related penetrance, meaning that not all individuals with a pathogenic mutation will develop disease, and that the risk for symptoms of the disease increases with age.

Clinical Sensitivity

A genetic mutation causing hypertrophic cardiomyopathy can be identified in approximately 60% of probands with familial disease, and in 20-30% of isolated cases (Gersh et al, 2011). The Hypertrophic Cardiomyopathy panel includes the genes most commonly involved in hypertrophic cardiomyopathy. Mutations in genes included in the HCM core panel are expected to account for >90% of cases of hypertrophic cardiomyopathy where a causative mutation can be identified (with mutations in MYH7 and MYBPC3 accounting for 80% of cases).

Methodology & Analytical Sensitivity

Next-generation sequencing technology is used to test clinically relevant portions of each gene, including coding exons, adjacent intron/exon boundaries, and selected introns/noncoding variants. Pathogenic and likely pathogenic variants are confirmed by orthogonal methods. Copy number variants, including intragenic deletions and duplications are detected to a resolution of single exon. To request analysis of a specific single exon copy number variant, please contact our Client Services team prior to ordering. Analytical sensitivity of the assay is 99.5%.

Indications for Testing

  • Confirmation of a clinical diagnosis
  • Unexplained cardiac arrest
  • Risk assessment for asymptomatic family of members of proband with molecular diagnosis of hypertrophic cardiomyopathy

Included Genes (27)

ACTC1 FLNC PLN
ACTN2 GAA PRKAG2
AGL GLA TCAP
BAG3 LAMP2 TNNC1
CACNA1C LDB3 TNNI3
CAV3 MYBPC3 TNNT2
CSRP3 MYH7 TPM1
DES MYL2 TTR
FHL1 MYL3 VCL

Additions to Hypertrophic Cardiomyopathy Panel

Emerging Evidence Genes (11)

Emerging evidence genes can also be added on to the comprehensive panel. These genes do not have a clear association with hypertrophic cardiomyopathy, but emerging evidence suggests that they may play a role in disease:

ANKRD1 MYOM1
CAL3 MYOZ2
GATA4 MYPN
JPH2 NEXN
MYH6 PDLIM3
MYLK2

RASopathies Add-On Panel (18)

Genes associated with the “RASopathy” spectrum of disorders, which frequently include hypertrophic cardiomyopathy as a symptom, may be added onto the Hypertrophic Cardiomyopathy panel.

Mutations in genes related to the Ras/MapK cell signaling pathway cause a group of related disorders known as the RASopathies. These disorders include Noonan syndrome, Cardiofaciocutaneous (CFC) syndrome, Costello syndrome, neurofibromatosis (NF), LEOPARD syndrome, and Legius syndrome, among others. The Ras/MapK pathway is involved in cell growth, differentiation, proliferation, and death. The Ras/MAPK spectrum of disorders shows both locus and allelic heterogeneity, meaning that mutations in different genes can cause the same phenotype, and different mutations in the same gene can cause different phenotypes,respectively. Although the specific phenotype varies by disease, many, but not all, of these disorders include hypertrophic cardiomyopathy as a feature.

A2ML1 MAP2K2 RIT1
BRAF NF1 RRAS
CBL NRAS SHOC2
HRAS PTPN11 SOS1
KRAS RAF1 SOS2
MAP2K1 RASA1 SPRED1

Syndromic Pediatric Add-On Panel (4)

Genes associated with pediatric syndromes inherited in an autosomal recessive manner that present with hypertrophic cardiomyopathy as feature can also be added to the Hypertrophic Cardiomyopathy Panel.

ACADVL CPT2 ELAC2 MTO1

References

  1. Ackerman MJ, Priori SG, Willems S, et al. HRS/EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA). Heart Rhythm. 2011;8(8):1308-39.
  2. Cirino AL, Ho C. Hypertrophic Cardiomyopathy Overview. 2008 Aug 5 [Updated 2014 Jan 16]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.
  3. Gersh BJ, Maron BJ, Bonow RO, et al. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2011;124(24):2761-96.
  4. Hershberger RE, Lindenfeld J, Mestroni L, et al. Genetic evaluation of cardiomyopathy–a Heart Failure Society of America practice guideline. J Card Fail. 2009;15(2):83-97.
  5. Morita H, Rehm HL, Menesses A, et al. Shared genetic causes of cardiac hypertrophy in children and adults. N Engl J Med. 2008;358(18):1899-908.
  6. Semsarian C, Ingles J, Maron MS, Maron BJ. New perspectives on the prevalence of hypertrophic cardiomyopathy. J Am Coll Cardiol. 2015;65(12):1249-54.