Hypertrophic Cardiomyopathy Panel, Sequencing

Last Literature Review: February 2021 Last Update:
  • 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.

If a familial sequence variant has been previously identified, targeted sequencing for that variant may be appropriate; refer to the Laboratory Test Directory for additional information.

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 diseaseLAMP2

Skeletal myopathy

Retinal dystrophy

Fabry diseaseGLA

Periodic pain crises

Agniokeratomas

Hypohidrosis

Ocular abnormalities

Proteinuria/decreased renal function

Glycogen storage disease IIGAA

Poor feeding

Macroglossia

Motor delay/muscle weakness

Respiratory difficulty

Glycogen storage disease of the heart, congenitalPRKAG2

Neonatal hypoglycemia

Vacuolar myopathy

Facial differences/macroglossia

Mitochondrial diseasemtDNA or nuclear genes associated with mitochondrial functionUp to 60% of individuals with a mitochondrial disorder may exhibit HCM
RASopathiesBRAF, 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 amyloidosisTTR

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 

Analytic Sensitivity

For massively parallel sequencing:

Variant ClassAnalytic Sensitivity (PPA) Estimatea (%)Analytic Sensitivity (PPA) 95% Credibility Regiona (%)
SNVs99.296.9-99.4
Deletions 1-10 bp93.884.3-98.2
Deletions 11-44 bp99.987.8-100
Insertions 1-10 bp94.886.8-98.5
Insertions 11-23 bp99.962.1-100

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
GeneMIM #Associated Disorder(s)Inheritance
ACTC1102540

HCM 11

DCM 1R

Atrial septal defect 5

AD
ACTN2102573

HCM 23 with or without LVNC

DCM 1AA with or without LVNC

AD
AGL610860Glycogen storage disease IIIAR
ALPK3617608HCM 27AR
BRAF164757

Cardiofaciocutaneous syndrome 1

Noonan syndrome 7

AD
CACNA1C114205

Timothy syndrome

LQTS 8

AD
CSRP3600824HCM 12AD
DES125660Myofibrillar myopathy 1AD/AR
DCM 1IAD
FHL1300163

Emery-Dreifuss muscular dystrophy 6

Reducing body myopathy 1B

Uruguay faciocardiomusculoskeletal syndrome

XL
FLNC102565

HCM 26

Restrictive cardiomyopathy 5

Distal myopathy 4

AD
GAA606800Glycogen storage disease II (Pompe)AR
GLA300644Fabry diseaseXL
HRAS190020Costello syndromeAD
JPH2605267HCM 17AD
KRAS190070

Cardiofaciocutaneous syndrome 2

Noonan syndrome 3

AD
LAMP2309060Danon diseaseXL
MAP2K1176872Cardiofaciocutaneous syndrome 3AD
MAP2K2601263Cardiofaciocutaneous syndrome 4AD
MYBPC3600958

HCM 4

DCM 1MM

AD
MYH7160760

HCM 1

DCM 1S

AD
Myosin storage myopathyAR
MYL2160781HCM 10AD
MYL3160790HCM 8AD
NRAS164790Noonan syndrome 6AD
PLN172405

HCM 18

DCM 1P

AD
PRKAG2602743

Lethal congenital glycogen storage disease of heart

HCM 6

Wolff-Parkinson-White syndrome

AD
PTPN11176876

Noonan syndrome 1

LEOPARD syndrome 1

AD
RAF1164760

Noonan syndrome 5

DCM 1NN

LEOPARD syndrome 2

AD
RIT1609591Noonan syndrome 8AD
SOS1182530Noonan Syndrome 4AD
TNNC1191040

HCM 13

DCM 1Z

AD
TNNI3191044

HCM 7

Restrictive cardiomyopathy 1

DCM 1FF

AD
DCM 2AAR
TNNT2191045

HCM 2

Restrictive cardiomyopathy 3

DCM 1D

AD
TPM1191010

HCM 3

DCM 1Y

AD
TTR176300Transthyretin-related amyloidosisAD
AD, autosomal dominant; AR, autosomal recessive; DCM, dilated cardiomyopathy; LQTS, long QT syndrome; LVNC, left ventricular noncompaction; XL, X-linked

References