1. NGS Panel – Genetic Testing for Dilated Cardiomyopathy

Dilated Cardiomyopathy

May 12, 2017

Disease synonyms

Familial dilated cardiomyopathy, FDC, Cardiomyopathy dilated, CMD, Dilated cardiomyopathy, DCM

Inheritance pattern

Autosomal dominant, autosomal recessive or X-linked manner

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.

Dilated cardiomyopathy is defined by the presence of left ventricular dilatation and resulting contractile dysfunction. Genetic mutations involving genes that encode cytoskeletal, sarcomere, and nuclear envelope proteins, among others, account for up to 35% of dilated cardiomyopathy cases1. Idiopathic dilated cardiomyopathy has become one of the most prevalent inherited cardiomyopathies over the past decades. Genetic screening of first-degree relatives has revealed that 30-50% of the cases have a familial origin 2. The prevalence of DCM is estimated at 1:250 3.

Dilated cardiomyopathy (DCM) may be asymptomatic for a number of years. Presentation usually occurs late in the disease course with any one of the following:

  • Heart failure, characterized by symptoms that include edema, orthopnea, paroxysmal nocturnal dyspnea, fatigue and dyspnea on exertion
  • Arrhythmias and/or conduction system disease symptoms that almost exclusively accompany progressive cardiomyopathy and heart failure
  • Thromboembolic disease, including stroke or systemic embolus, and secondary to left ventricular mural thrombus.

More than 50% of DCM-affected cases are genetically determined, and so far more than 40 genes have been identified affecting proteins of a wide variety of cellular structures that regulate cardiac muscle function, such as the sarcomere, the nuclear envelope, the cytoskeleton, the sarcolemma and the intercellular junction4.

A range of approximately 10-20% of DCM, regardless of family history, has been attributed to pathogenic truncating variants in the TTN gene, encoding for protein tintin4, 5. Titin is the largest-known human protein, highly expressed in the sarcomere of the heart muscle. TTN provides both passive force and elasticity to preserve diastolic and systolic function. Also, titin regulates the assembly and length of the sarcomere. While the role of truncation mutations in DCM is accepted, the pathogenic and prognostic role of missense variants is still debated and under investigation.

One of the most commons genes implicated in familial DCM is LMNA, encoding the intermediate filament proteins lamin A. LMNA mutations account for 6% of familial DCM cases1, 6, 7. LMNA gene mutations may be associated with extracardiac features, including skeletal muscle weakness and contractures in the form of Emery-Dreifuss muscular dystrophy or limb girdle muscular dystrophy type. LMNA mutations can also produce Hutchinson-Guilford progeria syndrome, lipodystrophy, and Charcot-Marie-Tooth syndrome type 2B. Cardiovascular disease with LMNA mutations can be limited to DCM with or without conduction system disease.

Mutations in the sarcomere genes cause both hypertrophic cardiomyopathy (HCM) and DCM. Sarcomere mutations have been identified in 25% of idiopathic DCM cases1 and account for 10% of familial DCM1, 7. The most common sarcomere genes identified in familial DCM are β-myosin heavy chain (MYH7) (~4%)1, 7 and Troponin T (TNNT2) (2.9%)1, 7. Other sarcomere genes identified in familial DCM are α-tropomyosin (TPM1), troponin C (TNNC1), troponin I (TNNI3), cardiac actin (ACTC), and others. Furthermore, an analysis of Becker muscular dystrophy gene mutations has indicated the regions of the dystrophin protein that may be prone to cardiomyopathy7. Additional genes which act as part of calcium regulation and ion channels have been identified as causative of DCM.

Treatment of dilated cardiomyopathy and resulting chronic heart failure includes medications that improve survival, such as angiotensin converting enzyme inhibitors (ACE) and β blockers8, and must be used as a preventive measure. Other interventions include arrhythmia management using device therapy and sudden death prevention. Patients who are refractory to medical therapy might benefit from mechanical circulatory support and heart transplantation. Treatment of preclinical disease and the potential role of stem-cell therapy are being investigated8.

CENTOGENE offers sequencing in the Cardiomyopathy dilated panel (genes: ABCC9, ACTC1, ACTN2, ANKRD1, BAG3, CRYAB, CSRP3, DES, DMD, DNAJC19, DOLK, DSC2, DSG2, DSP, EMD, EYA4, FKTN, GATA4, GATAD1, ILK, LAMA4, LAMP2, LDB3, LMNA, MURC, MYBPC3, MYH6, MYH7, MYPN, NEBL, NEXN, PDLIM3, PKP2, PLN, PRDM16, RAF1, RBM20, SCN5A, SGCD, TAZ, TBX20, TCAP, TNNC1, TNNI3, TNNT2, TPM1, TTN, TTR, TXNRD2, VCL) and deletion/duplication test of selected genes from the panel: MYBPC3, TNNT2, SGCD, MYH7, RAF1, BAG3, DMD, DSC2, DSG2, SCN5A, LMNA, PKP2, FKTN, DSP, GATA4).

Overview of genes included in Cardiomyopathy dilated panel

Gene OMIM (Gene) Associated diseases (OMIM) Inheritance CentoMD® exclusive variant numbers (++)
ABCC9 601439 Cantu syndrome/ Hypertrichotic osteochondrodysplasia; dilated cardiomyopathy-1O AD 17
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
BAG3 603883 Myopathy, myofibrillar, 6; dilated cardiomyopathy-1HH AD 8
CAVIN4 617714 1
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
DMD 300377 Becker muscular dystrophy; dilated cardiomyopathy type 3B; Duchenne muscular dystrophy XL, XLR 436
DNAJC19 608977 3-methylglutaconic aciduria, type 5 AR 2
DOLK 610746 congenital disorder of glycosylation type 1m AR 1
DSC2 125645 Arrhythmogenic right ventricular dysplasia 11 AD, AR 11
DSG2 125671 Arrhythmogenic right ventricular dysplasia 10; dilated cardiomyopathy AD 12
DSP 125647 dilated cardiomyopathy with woolly hair and keratoderma; arrhythmogenic right ventricular dysplasia type 8; lethal acantholytic epidermolysis bullosa; Keratosis palmoplantaris striata II AD, AR 18
EMD 300384 Emery-Dreifuss muscular dystrophy type 1 XLR 6
EYA4 603550 Deafness, autosomal dominant 10; dilated cardiomyopathy-1J AD 10
FKTN 607440 congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A4; congenital limb-girdle muscular dystrophy-dystroglycanopathy type C4; dilated cardiomyopathy type 1X; congenital muscular dystrophy-dystroglycanopathy without mental retardation type B4 AR 13
GATA4 600576 Tetralogy of Fallot; Atrial septal defect 2; Ventricular septal defect 1; Atrioventricular septal defect 4 AD 0
GATAD1 614518 dilated cardiomyopathy-2B AR 2
ILK 602366 0
LAMA4 600133 dilated cardiomyopathy-1JJ AD 1
LAMP2 309060 Danon disease XLD 10
LDB3 605906 dilated cardiomyopathy-1C; Myopathy, myofibrillar, 4 AD 11
LMNA 150330 dilated cardiomyopathy-1A; Lipodystrophy, familial partial, 2; Hutchinson-Gilford progeria; Emery-Dreifuss muscular dystrophy 2; Malouf syndrome; Mandibuloacral dysplasia; Restrictive dermopathy, lethal; type 2B1 Charcot-Marie-Tooth disease; Heart-hand syndrome, Slovenian type; Muscular dystrophy, congenital; Emery-Dreifuss muscular dystrophy 3, AR AD, AR 22
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
MYPN 608517 dilated cardiomyopathy-1KK AD, AR 3
NEBL 605491 0
NEXN 613121 dilated cardiomyopathy-1CC; familial hypertrophic cardiomyopathy 20 AD 10
PDLIM3 605889 0
PKP2 602861 arrrhythmogenic right ventricular dysplasia 9 AD 9
PLN 172405 dilated cardiomyopathy-1P; Cardiomyopathy, familial hypertrophic, 18 AD 0
PRDM16 605557 left ventricular noncompaction 8 AD 2
RAF1 164760 Noonan syndrome 5; Cardiomyopathy, dilated, 1NN AD 8
RBM20 613171 dilated cardiomyopathy-1DD AD 11
SCN5A 600163 susceptibility to sudden infant death syndrome; Brugada syndrome 1; dilated cardiomyopathy-1E; long QT syndrome 3; Sick sinus syndrome 1 AD, AR 27
SGCD 601411 limb-girdle muscular dystrophy type 2F; dilated cardiomyopathy-1L AR 5
TAZ 300394 Barth syndrome XLR 4
TBX20 606061 Atrial septal defect 4 1
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
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
TXNRD2 606448 AR 0
VCL 193065 dilated cardiomyopathy-1W; Cardiomyopathy, familial hypertrophic, 15 AD 18

Differential diagnosis

The differential diagnosis of dilated cardiomyopathy related disorders – depending on the major symptoms in the initial case – includes the following diseases1:

  • HFE-associated hereditary hemochromatosis
  • Emery-Dreifuss muscular dystrophy
  • Limb girdle muscular dystrophy 1B
  • Laing distal myopathy
  • Carvajal syndrome
  • Becker muscular dystrophy (late onset of dilated cardiomyopathy)
  • Barth syndrome

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 dilated cardiomyopathy 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 dilated panel. Copy Number Variants analysis derived from NGS data is also included.

Step 2: If no mutation is identified after analysis of the Cardiomyopathy dilated 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 dilated 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.