Hypertrophic Cardiomyopathy Panel, Sequencing

  • Use to determine etiology of hypertrophic cardiomyopathy (HCM) in symptomatic individuals.
  • Useful for presymptomatic testing in individuals with a family history of HCM or sudden cardiac death.
  • Test includes genes associated with familial HCM and common syndromic forms of HCM (including Noonan syndrome/RASopathy); mitochondrial genes are not interrogated.

Preferred test to assess for hereditary forms of cardiomyopathy or arrhythmia.

  • Use to assess for a familial sequence variant previously identified in a family member.
  • A copy of the relative's genetic laboratory report documenting the familial variant is required.

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)
Select Syndromes Associated with HCM
Syndrome(s) Gene(s) Clinical Features

Danon disease

LAMP2

Skeletal myopathy

Retinal dystrophy

Fabry disease

GLA

Periodic pain crises

Agniokeratomas

Hypohidrosis

Ocular abnormalities

Proteinuria/decreased renal function

Glycogen storage disease II

GAA

Poor feeding

Macroglossia

Motor delay/muscle weakness

Respiratory difficulty

Glycogen storage disease of the heart, congenital

PRKAG2

Neonatal hypoglycemia

Vacuolar myopathy

Facial differences/macroglossia

Mitochondrial disease

mtDNA or nuclear genes associated with mitochondrial function

Up to 60% of individuals with a mitochondrial disorder may exhibit HCM

RASopathies

BRAF, HRAS, KRAS, MAP2K1, MAP2K2, NRAS, PTPN11, RAF1, RIT1, SOS1

20-30% of individuals with Noonan syndrome have HCM

Other features include variable developmental delay, short stature, characteristic facial features, and cutaneous abnormalities

Transthyretin amyloidosis

TTR

Progressive peripheral sensorimotor neuropathy and autonomic neuropathy

Vitreous opacities

CNS amyloidosis

CNS, central nervous system

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 

Analytical Sensitivity

For massively parallel sequencing:

Variant Class Analytical Sensitivity (PPA) Estimatea (%) Analytical Sensitivity (PPA) 95% Credibility Regiona (%)

SNVs

99.2

96.9-99.4

Deletions 1-10 bp

93.8

84.3-98.2

Deletions 11-44 bp

99.9

87.8-100

Insertions 1-10 bp

94.8

86.8-98.5

Insertions 11-23 bp

99.9

62.1-100

aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived.

bp, base pairs; PPA, positive percent agreement; SNVs, single nucleotide variants

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
Genes Tested
Gene MIM # Associated Disorder(s) Inheritance

ACTC1

102540

HCM 11

DCM 1R

Atrial septal defect 5

AD

ACTN2

102573

HCM 23 with or without LVNC

DCM 1AA with or without LVNC

AD

AGL

610860

Glycogen storage disease III

AR

ALPK3

617608

HCM 27

AR

BRAF

164757

Cardiofaciocutaneous syndrome 1

Noonan syndrome 7

AD

CACNA1C

114205

Timothy syndrome

LQTS 8

AD

CSRP3

600824

HCM 12

AD

DES

125660

Myofibrillar myopathy 1

AD/AR

DCM 1I

AD

FHL1

300163

Emery-Dreifuss muscular dystrophy 6

Reducing body myopathy 1B

Uruguay faciocardiomusculoskeletal syndrome

XL

FLNC

102565

HCM 26

Restrictive cardiomyopathy 5

Distal myopathy 4

AD

GAA

606800

Glycogen storage disease II (Pompe)

AR

GLA

300644

Fabry disease

XL

HRAS

190020

Costello syndrome

AD

JPH2

605267

HCM 17

AD

KRAS

190070

Cardiofaciocutaneous syndrome 2

Noonan syndrome 3

AD

LAMP2

309060

Danon disease

XL

MAP2K1

176872

Cardiofaciocutaneous syndrome 3

AD

MAP2K2

601263

Cardiofaciocutaneous syndrome 4

AD

MYBPC3

600958

HCM 4

DCM 1MM

AD

MYH7

160760

HCM 1

DCM 1S

AD

Myosin storage myopathy

AR

MYL2

160781

HCM 10

AD

MYL3

160790

HCM 8

AD

NRAS

164790

Noonan syndrome 6

AD

PLN

172405

HCM 18

DCM 1P

AD

PRKAG2

602743

Lethal congenital glycogen storage disease of heart

HCM 6

Wolff-Parkinson-White syndrome

AD

PTPN11

176876

Noonan syndrome 1

LEOPARD syndrome 1

AD

RAF1

164760

Noonan syndrome 5

DCM 1NN

LEOPARD syndrome 2

AD

RIT1

609591

Noonan syndrome 8

AD

SOS1

182530

Noonan Syndrome 4

AD

TNNC1

191040

HCM 13

DCM 1Z

AD

TNNI3

191044

HCM 7

Restrictive cardiomyopathy 1

DCM 1FF

AD

DCM 2A

AR

TNNT2

191045

HCM 2

Restrictive cardiomyopathy 3

DCM 1D

AD

TPM1

191010

HCM 3

DCM 1Y

AD

TTR

176300

Transthyretin-related amyloidosis

AD

AD, autosomal dominant; AR, autosomal recessive; DCM, dilated cardiomyopathy; LQTS, long QT syndrome; LVNC, left ventricular noncompaction; XL, X-linked

References

Additional Resources