1. NGS panel - Genetic testing for dilated cardiomyopathy

Dilated 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.

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 the genes in CENTOGENE´s Cardiomyopathy dilated panel

Gene Protein OMIM
chr. locus
% of mutations Allelic disorders
ABCC9 ATP-binding protein 9 601439
Rare1 Atrial fibrillation, familial, 12
Cardiomyopathy, dilated, 1O
Hypertrichotic osteochondrodysplasia
ACTC1 Actin, alpha cardiac muscle 1 102540
<1%1 Cardiomyopathy, dilated, 1R/hypertrophic, 11
Atrial septal defect 5
Left ventricular noncompaction 4
ACTN2 Alpha-actinin-2 102573
<1%1 Cardiomyopathy, dilated, 1AA
Cardiomyopathy, hypertrophic, 23
ANKRD1 Ankyrin repeat domain protein 1 609599
2.2%1 ANKRD1-related cardiomyopathy
BAG3 BAG family molecular chaperone regulator 3 603883
2.5%1 Cardiomyopathy, dilated, 1HH
Myopathy, myofibrillar, 6
CRYAB Crystallin alpha-B 123590
Rare1 Cardiomyopathy, dilated, 1II
Myopathy, myofibrillar, 2
Myopathy, myofibrillar, fatal infantile
CSRP3 Cysteine-rich protein 3 600824
<1%1, 2 Cardiomyopathy, dilated, 1M
Cardiomyopathy, hypertrophic, 12
DES Desmin 125660
<1%1 Cardiomyopathy, dilated, 1I,
Myopathy, myofibrillar, 1
Muscular dystrophy, limb-girdle, type 2R
DMD Dystrophin 300377
Rare1 Cardiomyopathy, dilated, 3B
Becker muscular dystrophy
Duchenne muscular dystrophy
DNAJC19 DNAJ/HSP40 protein19 608977
Rare1 Dilated cardiomyopathy ataxia syndrome
3-methylglutaconic aciduria, type V
DOLK Dolichol kinase 610746
Rare1 Dilated cardiomyopathy DOLK related
Congenital disorder of glycosylation, type Im
DSC2 Desmocollin 2 125645
1%1, 3 Arrhythmogenic right ventricular dysplasia 11
DSG2 Desmoglein 125671
4%1, 3 Cardiomyopathy, dilated, 1BB
Arrhythmogenic right ventricular dysplasia 10
DSP Despomplakin 125647
3%1, 3 Arrhythmogenic right ventricular dysplasia 8
Dilated cardiomyopathy with woolly hair, keratoderma, and tooth agenesis
Epidermolysis bullosa, lethal acantholytic
EMD Emerin 300384
Rare1 Dilated cardiomyopathy EMD related
Emery-Dreifuss muscular dystrophy 1
EYA4 Eyes absent protein 4 603550
Rare1 Cardiomyopathy, dilated, 1J
Deafness, autosomal dominant 10
FKTN Fukutin 607440
Rare (1/172)4 Cardiomyopathy, dilated, 1X
Muscular dystrophy-dystroglycanopathy A4, B4
Muscular dystrophy-dystroglycanopathy C4
GATA4 GATA-binding protein 4 600576
Rare1 Atrial septal defect 2, Tetralogy of Fallot
Atrioventricular septal defect 4
Ventricular septal defect 1
GATAD1 GATA Zn finger domain protein 1 614518
Rare1 Cardiomyopathy, dilated, 2B
ILK Integrin linked kinase 602366
Rare1 Severe cardiomyopathy with dystrophy
LAMA4 Laminin alpha-4 600133
Rare1 Cardiomyopathy, dilated, 1JJ
LAMP2 Lysosome-associated membrane protein 2 309060
Rare1 Danon disease
LMNA Prelamin-A/C 150330
6%1, 5 Cardiomyopathy, dilated, 1A
Charcot-Marie-Tooth disease, type 2B1
Emery-Dreifuss muscular dystrophy 2, 3
Hutchinson-Gilford progeria
Muscular dystrophy, limb-girdle, type 1B
LDB3 LIM domain-binding protein 3 605906
1%1, 2 Cardiomyopathy, dilated, 1C/hypertrophic, 24
Left ventricular noncompaction 3
Myopathy, myofibrillar, 4
MURC Muscle related coiled-coil protein unknown Rare Cardiomyopathy-MURC related
MYBPC3 Myosin-binding protein C, cardiac-type 600958
2%-4%1 Cardiomyopathy, dilated, 1MM / hypertrophic, 4
Left ventricular noncompaction 10
MYH6 Myosin-6 160710
3%-4%1, 6 Atrial septal defect 3 , Sick sinus syndrome 3
Cardiomyopathy, dilated, 1EE / hypertrophic, 14
MYH7 Myosin-7 160760
4.2%1, 2, 6 Cardiomyopathy, dilated, 1S / hypertrophic, 1
Laing distal myopathy , Myopathy, myosin storage Left ventricular noncompaction 5
MYPN Myopalladin 608517
Rare7 Cardiomyopathy, dilated, 1KK / , hypertrophic, 22
Cardiomyopathy restrictive, 4
Nemaline myopathy 11
NEBL Nebulette 605491
1,8%1, 8 Cardiomyopathy NEBL related
NEXN Nexilin 613121
<1% (2/121)9 Cardiomyopathy, dilated, 1CC
Cardiomyopathy, hypertrophic, 20
PDLIM3 PDZ domain protein 3 605889
Rare1 Cardiomyopathy PDLIM3 related
PKP2 Plakophilin 2 602861
Rare1 Arrhythmogenic right ventricular dysplasia 9
PLN Phosphoamban 172405
Rare1 Cardiomyopathy, dilated, 1P
Cardiomyopathy, hypertrophic, 18
PRDM16 PR-domain containing protein 16 605557
Rare1 Cardiomyopathy, dilated, 1LL
Left ventricular noncompaction 8
PSEN1 Presenilin-1 104311
<1%1 Early-onset Alzheimer disease
PSEN2 Presenilin-2 600759
<1%1 Early- and late-onset Alzheimer disease
RAF1 Oncogene RAF1 164760
~9%1 Cardiomyopathy, dilated, 1NN
Noonan syndrome 5
LEOPARD syndrome 2
RBM20 RNA-binding protein 20 613171
1.9%1 Cardiomyopathy, dilated, 1DD
SCN5A Sodium channel protein type 5 subunit alpha 600163
2%-4%1, 2 UAtrial fibrillation, familial, 10
Brugada syndrome 1
Long QT syndrome-3, Ventricular fibrillation 1
Cardiomyopathy, dilated, 1E, Heart block type IA
Sudden infant death syndrome
SGCD Sarcoglycan delta 601411
Rare10 Cardiomyopathy, dilated, 1L
Muscular dystrophy, limb-girdle, type 2F
TAZ Tafazzin 300394
4/11411 Barth syndrome
Cardiomyopathy with neutropenia myopathy
TBX20 T-box 20 protein 606061
Rare12 Atrial septal defect 4
TCAP Telethonin 604488
1%1, 2 Cardiomyopathy, hypertrophic, 25
Muscular dystrophy, limb-girdle, type 2G
TNNC1 Troponin C, slow skeletal and cardiac muscles 191040
<1%-1.3%1, 2 Cardiomyopathy, dilated, 1Z
Cardiomyopathy, hypertrophic, 13
TNNI3 Troponin I, cardiac muscle 191044
1.3%1, 2 Cardiomyopathy, dilated, 1FF
Cardiomyopathy, familial restrictive, 1
Cardiomyopathy, hypertrophic, 7
TNNT2 Troponin T, cardiac muscle 191045
2.9%1, 2 Cardiomyopathy, dilated, 1D / hypertrophic, 2
Cardiomyopathy, familial restrictive, 3
Left ventricular noncompaction 6
TPM1 Tropomyosin alpha-1 chain 191010
<1%-1.9%1, 2 Cardiomyopathy, dilated, 1Y
Cardiomyopathy, hypertrophic, 3
Left ventricular noncompaction 9
TTN Titin 188840
10%-20%1, 13, 14 Cardiomyopathy, dilated, 1G / hypertrophic, 9
Muscular dystrophy, limb-girdle, type 2J
Myopathy with fatal cardiomyopathy
Myopathy with respiratory involvement
Tibial muscular dystrophy, tardive
TTR Transthyretin 176300
Rare1 Transthyretin related cardiomyopathy
Amyloidosis, hereditary, transthyretin-related
Dystransthyretinemic hyperthyroxinemia
TXNRD2 Thioredoxin reductase 2 606448
Rare (2/227)15 Dilated cardiomyopathy
VCL Vinculin 193065
1%1, 5 Cardiomyopathy, dilated, 1W
Cardiomyopathy, hypertrophic, 15

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.

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