1. NGS Panel – Genetic Testing for Hypertrophic Cardiomyopathy

Hypertrophic Cardiomyopathy

May 12, 2017

Disease synonyms

Cardiomyopathy, familial hypertrophic, CMH, Ventricular hereditary hypertrophy, Asymmetric septal hypertrophy; ASH, Hypertrophic subaortic stenosis, Hereditary hypetrophic cardiomyopathy, HCM

Inheritance pattern

Autosomal dominant

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 genes included in Hypertrophic cardiomyopathy panel

Gene OMIM (Gene) Associated diseases (OMIM) Inheritance CentoMD® exclusive variant numbers (++)
ACTC1 102540 familial hypertrophic cardiomyopathy 11; Atrial septal defect 5; dilated cardiomyopathy-1R AD 3
ACTN2 102573 dilated cardiomyopathy-1AA AD 16
ANKRD1 609599 0
CALR3 611414 10
CAV3 601253 Creatine phosphokinase, elevated serum; familial hypertrophic cardiomyopathy 1; Rippling muscle disease; long QT syndrome 9 AD 12
CRYAB 123590 Myopathy, myofibrillar, 2; Cataract 16, multiple types; Myopathy, Myofibrillar, Fatal Infantile Hypertonic, Alpha-B Crystallin-Related; dilated cardiomyopathy-1II AD, AR 1
CSRP3 600824 dilated cardiomyopathy-1M; Cardiomyopathy, familial hypertrophic, 12 AD 4
DES 125660 Scapuloperoneal syndrome, neurogenic, Kaeser type; Myopathy, myofibrillar, 1; dilated cardiomyopathy-1I AD, AR 4
FHL2 602633 1
FLNC 102565 Myopathy, myofibrillar, 5; Cardiomyopathy, Familial Hypertrophic, 26 AD 9
GLA 300644 Fabry disease XL 583
JPH2 605267 Cardiomyopathy, familial hypertrophic 17 AD 6
LAMP2 309060 Danon disease XLD 10
LDB3 605906 dilated cardiomyopathy-1C; Myopathy, myofibrillar, 4 AD 11
MYBPC3 600958 familial hypertrophic cardiomyopathy 4; dilated cardiomyopathy-1MM AD 18
MYH6 160710 Cardiomyopathy, familial hypertrophic, 14; dilated cardiomyopathy-1EE; Atrial septal defect 3 AD 25
MYH7 160760 Liang distal myopathy; Scapuloperoneal syndrome, myopathic type; familial hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal dominant; dilated cardiomyopathy-1S AD, AR 38
MYL2 160781 Cardiomyopathy, familial hypertrophic, 10 AD 5
MYL3 160790 familial hypertrophic cardiomyopathy 8 AD, AR 2
MYLK2 606566 familial hypertrophic cardiomyopathy 1 AD 6
MYPN 608517 dilated cardiomyopathy-1KK AD, AR 3
NEXN 613121 dilated cardiomyopathy-1CC; familial hypertrophic cardiomyopathy 20 AD 10
PDLIM3 605889 0
PLN 172405 dilated cardiomyopathy-1P; Cardiomyopathy, familial hypertrophic, 18 AD 0
PRKAG2 602743 Wolff-Parkinson-White syndrome; fatal congenital hypertrophic cardiomyopathy due to glycogen storage disease; familial hypertrophic cardiomyopathy 6 ?AD, AD 18
SLC25A4 103220 Progressive External Ophthalmoplegia With Mitochondrial Dna Deletions, Autosomal Dominant, 2; mitochondrial DNA depletion syndrome 12; mitochondrial DNA depletion syndrome type 12A AD, AR 12
SOS1 182530 Noonan syndrome 4 AD 18
TCAP 604488 limb-girdle muscular dystrophy type 2G; cardiomyopathy, familial hypertrophic, 25 AD, AR 6
TNNC1 191040 dilated cardiomyopathy-1Z; familial hypertrophic cardiomyopathy 13 AD 3
TNNI3 191044 dilated cardiomyopathy-2A; familial hypertrophic cardiomyopathy 7 AD, AR 13
TNNT2 191045 familial hypertrophic cardiomyopathy 2; dilated cardiomyopathy-1D AD 27
TPM1 191010 Cardiomyopathy, familial hypertrophic, 3; dilated cardiomyopathy-1Y AD 23
TRIM63 606131 0
TTN 188840 Tibial muscular dystrophy, tardive; Hereditary myopathy with early respiratory failure; dilated cardiomyopathy type 1G; limb-girdle muscular dystrophy type 2J; early-onset myopathy with fatal cardiomyopathy; familial hypertrophic cardiomyopathy type 9 AD, AR 115
TTR 176300 familial transthyretin amyloidosis AD 14
VCL 193065 dilated cardiomyopathy-1W; Cardiomyopathy, familial hypertrophic, 15 AD 18

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.