Hypertrophic Cardiomyopathy Panel, Sequencing

Hypertrophic cardiomyopathy (HCM) is a genetically heterogeneous disorder characterized by left ventricular hypertrophy (LVH) in the absence of loading conditions, such as hypertension. Although some individuals with HCM remain asymptomatic, symptoms, when present, can include shortness of breath, chest pain, palpitations, orthostasis, and syncope. Affected individuals are at risk for arrhythmias, outflow tract obstruction, thromboembolic complications, heart failure, and sudden cardiac death.

Onset of familial idiopathic HCM may range from infancy to adulthood, although it often occurs in adolescence or early adulthood, and the risk for developing HCM is reduced after 50 years of age. Syndromic forms of HCM include extracardiac manifestations; however, such disorders can present as isolated LVH. Identification of syndromic forms of HCM is important because such disorders often have specific extracardiac management recommendations. Molecular testing for individuals with HCM is recommended to determine if a genetic etiology can be identified, which can facilitate patient management and screening of at-risk relatives.

Disease Overview

Associated Disorders

Familial HCM

• Onset in adolescence or early adulthood is most common; risk for developing HCM after 50 years of age is reduced
• Most commonly implicated genes are those encoding sarcomeric proteins:
  • MYBPC3 (50% of HCM cases)
  • MYH7 (33% of HCM cases)

Genetics

Genes

See table of Genes Tested.

Etiology

• Pathogenic germline variants in sarcomeric genes or other genes associated with HCM 
• The most commonly implicated genes are those encoding sarcomeric proteins:
  • MYBPC3: 50% of HCM cases
  • MYH7: 33% of HCM cases

Penetrance

Variable; influenced by gene and age

Prevalence of HCM

1 in 500

Inheritance

• Familial HCM is typically autosomal dominant.
• Compound heterozygous or digenic heterozygous variants may result in severe and early onset disease.
• Genes with X-linked, autosomal recessive, or mitochondrial inheritance are also associated with HCM.
• De novo variation may be found in children or adults.
• Compound heterozygous or digenic heterozygous variants may result in severe and early onset disease.

Test Description

Clinical Sensitivity

50-60% for familial HCM, 20-30% for isolated HCM 

Analytic Sensitivity

For massively parallel sequencing:

Limitations

• A negative result does not exclude a heritable form of hypertrophic cardiomyopathy.
• Diagnostic errors can occur due to rare sequence variations.
• Interpretation of this test result may be impacted if this patient has had an allogeneic stem cell transplantation.
• The following will not be evaluated:
  • Variants outside the coding regions and intron-exon boundaries of targeted gene(s)
  • Variants in the mitochondrial genome
  • Regulatory region and deep intronic variants
  • Large deletions/duplications in any of the tested genes (Large deletions/duplications account for ~1% of causative variants for familial HCM. )
  • Noncoding transcripts
  • The following exons are not sequenced due to technical limitations of the assay:
    • BRAF (NM_004333) exon(s) 5, 18
    • FLNC (NM_001458) exon(s) 47, 48
    • PRKAG2 (NM_016203) exon(s) 10, 13
• The following may not be detected:
  • Deletions/duplications/insertions of any size by massively parallel sequencing
  • Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
  • Low-level somatic variants