1. NGS panel - Genetic testing for hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy

May 12, 2017

Clinical features

Cardiomyopathies are disorders with primary abnormalities in the structure and function of the heart. These disorders are commonly grouped into morphological subtypes which include hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), restrictive cardiomyopathy (RCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), and left ventricular noncompaction cardiomyopathy (LVNC) 1.

Hypertrophic cardiomyopathy (HCM) is a global disease with cases reported in all continents, affecting people of both sexes and of various racial and ethnic origins. The incidence of HCM is approximately 1 in 500 in the general population2.

HCM is most commonly caused by pathogenic variants in one of the genes that encode different components of the sarcomere. The most common pathogenic mutations causing HCM were identified in genes encoding for the following: β-myosin heavy chain (MYH7, α-tropomyosin (TPM1), cardiac troponin T (TNNT2), cardiac myosin binding protein-C (MYBPC3), myosin regulatory light chain (MYL2), myosin essential light chain (MYL3), cardiac troponin I (TNNI3) and cardiac α-actin (ACTC1)5. Combined, MYBPC3 and MYH7 account for up to 50% of all clinically recognized cases of HCM, and constitute at least 75% of those affected where a mutation is identified2,5. Mutation of one of the genes that encodes a component of the sarcomere are found in approximately 50-60% of those affected with a family history of HCM, and 20-30% of those affected without a positive family history2, 3. Additional candidate genes, encoding proteins involved in cardiac muscle function, have been identified. CENTOGENE´s Cardiomyopathy hypertrophic panel includes the 36 genes most commonly associated with familial forms of HCM.

The clinical manifestations of HCM range from asymptomatic or progressive heart failure to sudden cardiac death (SCD). Clinical findings could significantly vary within the same family. Common symptoms include shortness of breath, chest pain, palpitations, orthostasis and syncope. Approximately 25% of persons affected with HCM show intracavitary obstruction at rest2. The degree of obstruction does not strictly correlate with the severity of symptoms or risk of sudden cardiac death. Patients affected with HCM are at an increased risk of atrial fibrillation (AF), which can have significant morbidity due to the increased risk of thromboembolism and symptomatic deterioration. The prevalence of AF increases with age. Furthermore, 5-10% of individuals with HCM progress to end-stage disease with impaired systolic function and, in some cases, left ventricular dilatation. The annual mortality rate in individuals with end-stage disease is estimated at 11% 4.

Treatment of HCM includes standard observation by a team of cardiologists, pharmacologic therapy, pacemakers or implantable cardiac defibrillators, and invasive septal reduction therapy. Cardiac transplantation may be necessary for patients with advanced refractory heart failure.

CENTOGENE offers sequencing of the Cardiomyopathy hypertrophic panel (genes: ACTC1, ACTN2, ANKRD1, CALR3, CAV3, CRYAB, CSRP3, DES, FHL2, FLNC, GLA, JPH2, LAMP2, LDB3, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYLK2, MYPN, NEXN, PDLIM3, PLN, PRKAG2, SLC25A4, SOS1, TCAP, TNNC1, TNNI3, TNNT2, TPM1, TRIM63, TTN, TTR, VCL), and deletion/duplication analysis of selected genes (MYBPC3, MYH7, SLC25A4, TNNT2, CAV3, GLA).

Overview of molecular genetics of hypertrophic cardiomyopathy (list of genes included in CENTOGENE´s Cardiomyopathy hypertrophic panel)

Gene Protein Chr. locus Inheritance Diseases % of mutations
ACTC1 Actin, alpha, cardiac muscle 15q14 AD Cardiomyopathy hypertrophic 11
Cardiomyopathy dilated 1R
Atrial septal defect 5
ACTN2 Actinin, alpha-2 1q43 AD Cardiomyopathy hypertrophic 23
Cardiomyopathy dilated 1AA
ANKRD1 Ankyrin repeat domain-protein 1 10q23.3 AD Cardiomyopathy Rare
CAV3 Caveolin 3 3p25.3 AD, AR Cardiomyopathy, familial hypertrophic
Long QT syndrome 9
7.5% in Italian cohort2
CSRP3 Cysteine-and glycine-rich protein 3 11p15.1 AD Cardiomyopathy hypertrophic 12
Cardiomyopathy dilated 1M
DES Desmin 2q35 AD, AR Cardiomyopathy dilated
Arrhythmogenic right ventricular cardiomyopathy
GLA Galactosidase, alpha Xq22.1 X-linked Fabry disease cardiac variant 0,9%2
LAMP2 Lysosome-associated membrane protein 2 Xq24 X-linked Danon disease 6%2
MYBPC3 Myosin-binding protein-C 11p11.2 AD Cardiomyopathy dilated 1MM
Cardiomyopathy hypertrophic 4
MYH7 Myosin, heavy chain 7 14q11.2 AD Cardiomyopathy hyertrophic 1
Cardiomyopathy dilated 1S
MYL2 Myosin, light chain 2 12q24.1 AD Cardiomyopathy hyertrophic 10 Rare
MYL3 Myosin, light chain 3, alkali, ventricular, skeletal, slow 3p21.31 AD, AR Cardiomyopathy, hypertrophic, 8 1%2
MYLK2 Myosin light chain kinase 2 20q11.21 AD Cardiomyopathy, hypertrophic, 1, digenic Rare
MYOZ2 Myozenin 2 4q26 AD Cardiomyopathy, hypertrophic, 16 Rare
NEXN Nexilin 1p31.1 AD Cardiomyopathy, hypertrophic, 20
Cardiomyopathy, dilated, 1CC
PLN Phospholamban 6q22.31 AD Cardiomyopathy, hypertrophic, 18
Cardiomyopathy, dilated, 1P
PRKAG2 Protein kinase, amp-activated 7q36.1 AD Cardiomyopathy, hypertrophic 6
Wolff-Parkinson-White syndrome
Glycogen storage disease of heart, lethal congenital
RAF1 V-RAF-1 homolog 1 3p25.2 AD Cardiomyopathy, dilated, 1NN
Noonan syndrome 5
TCAP Telethonin 17q12 AD, AR Cardiomyopathy, hypertrophic, 25 Rare
TNNC1 Troponin C, slow 3p21.1 AD Cardiomyopathy, hypertrophic, 13
Cardiomyopathy, dilated, 1Z
TNNI3 Troponin I, cardiac 19q13.42 AD, AR Cardiomyopathy, dilated, 1FF
?Cardiomyopathy, dilated, 2A
Cardiomyopathy, familial restrictive, 1
Cardiomyopathy, hypertrophic, 7
TNNT2 Troponin T2, cardiac 1q32.1 AD Cardiomyopathy, hypertrophic, 2
Cardiomyopathy, familial restrictive, 3
Cardiomyopathy, dilated, 1D
TPM1 Tropomyosin 1 15q22.2 AD Cardiomyopathy, familial hypertrophic, 3
Cardiomyopathy, dilated, 1Y
TTN Titin 2q31.2 AD, AR Cardiomyopathy, familial hypertrophic, 9
Cardiomyopathy, dilated, 1G
TTR Transthyretin 18q12.1 AD Transthyretin-related amyloidosis Rare
VCL Vinculin 10q22.2 AD Cardiomyopathy, dilated, 1W
Cardiomyopathy, hypertrophic, 15

Differential diagnosis

The differential diagnosis of hypertrophic cardiomyopathy related disorders – depending on the major symptoms in the initial case – includes the following diseases11, 2, 3:

  • Acquired left ventricular hypertrophy (LVH).
  • Aortic stenosis
  • Hypertensive heart disease
  • Syndromes with LVH (i.e., LVH associated with an underlying metabolic disorder or muscle disease including Fabry disease, cardiac amyloidosis, and Danon disease)
  • Childhood-onset conditions with LVH:

    • Inborn errors of metabolism
    • Malformation syndromes
    • Neuromuscular disorders

Testing strategy

CENTOGENE offers advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on the PCR-free Whole Genome Sequencing and NGS technology. This approach offers an unparalleled advantage by reducing amplification/capture biases and provides sequencing of entire gene at a more uniform coverage.

To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for cardiomyopathy hypertrophic using NGS Panel Genomic targeted towards this specific phenotype:

Step 1: Whole genome sequencing from a single filter card. The sequencing covers the entire genic region (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Cardiomyopathy hypertrophic panel. Copy Number Variants analysis derived from NGS data is also included.

Step 2: If no mutation is identified after analysis of the Cardiomyopathy hypertrophic panel, based on the approval and consent, we further recommend to continue the bioinformatics analysis of the data obtained by whole genome sequencing to cover genes that are either implicated in an overlapping phenotype or could be involved in a similar pathway but not strongly clinically implicated based on the current information in literature.

Referral reasons

The following individuals are candidates for hypertrophic cardiomyopathy panel genetic testing:

  • Individuals with a family history of disease and presentation of the most common symptoms
  • Individuals without a positive family history, but with symptoms resembling this disease
  • Individuals with a negative but suspected family history, in order to perform proper genetic counseling (prenatal analyses are recommended in families with affected individuals).

Test utility

Sequencing, deletion/duplication of this gene and related genes should be performed in all individuals suspected for this particular phenotype. In parallel, other genes reported to be related with this clinical phenotype should also be analyzed for the presence of mutations, due to the overlap in many clinical features caused by those particular genes.

Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management. Genetic counseling can provide a patient and/or family with the natural history of the condition, identify at-risk family members, provide reproductive risks as well as preconception/prenatal options, and allow for appropriate referral for patient support and/or resources.

More information on CENTOGENE´s panel for hypertrophic cardiomyopathy can be found in our genetic test catalogue.