Dilated Cardiomyopathy Panel, Sequencing

  • Use to determine etiology of DCM in symptomatic individuals.
  • Useful for presymptomatic testing in individuals with family history of DCM or sudden cardiac death.

Preferred test to assess for hereditary form of cardiomyopathy or arrhythmia.

  • Use to assess for a familial sequence variant previously identified in a family member.
  • A copy of the relative's genetic laboratory report documenting the familial variant is required.

Dilated cardiomyopathy (DCM) is characterized by left ventricular enlargement with impaired contractility and systolic dysfunction (typically defined as a left ventricular ejection fraction of <50%). DCM is a leading cause of symptoms requiring heart transplantation in children and adults. Although it is often an acquired condition, it may also be familial or a feature of a heritable syndrome. Familial DCM is most commonly inherited in an autosomal dominant manner. It typically manifests in adults during the fourth to sixth decade of life; however, it can present at any age and risk for developing DCM after 50 years of age is reduced.

Affected individuals are at risk for heart failure, arrhythmias or conduction disease, pregnancy-related cardiomyopathy, stroke, and sudden cardiac death. Symptoms may include dyspnea, chest pain, palpitations, fatigue, fainting, or edema. Some individuals remain asymptomatic. Syndromic forms of DCM include extracardiac manifestations, and identification of such disorders is important to enable appropriate management.

Molecular testing for individuals with DCM 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

Nonsyndromic Familial DCM

Should be considered if two or more individuals within a single family experience DCM or if a relative of an individual with DCM has experienced unexplained sudden death <35 years of age

Select Syndromes Associated with DCM
Syndrome Gene Clinical Features

Almstrom syndrome

ALMS1

Cone-rod dystrophy

Obesity

Progressive sensorineural hearing loss

Type 2 diabetes mellitus

Short stature

Barth syndrome

TAZ

Neutropenia

Muscle weakness

Growth delay

Infantile/early childhood onset

Carvajal syndrome

DSP

Woolly hair

Palmoplantar keratoderma

Congenital disorder of glycosylation 1M

DOLK

Ichtyosiform skin

Failure to thrive

Seizures

Developmental delay

Hypotonia

Duchenne/Becker muscular dystrophy

DMD

Muscle weakness

Isolated DCM in females

Emery-Dreifuss muscular dystrophy 1

EMD

Joint contractures

Childhood-adult onset muscle weakness

Conduction disease

Genetics

Genes

See table of Genes Tested.

Etiology

Pathogenic germline variants in genes associated with familial DCM:

  • Genetically heterogeneous disease with unique or "private" variants being common 
  • Genes implicated include those encoding components of the cytoskeleton, sarcomere, Z-disk, nuclear envelope, and those involved with calcium regulation/ion channels.

Other heritable forms of cardiomyopathy may have phenotypic overlap with DCM :

  • Cases of arrhythmogenic right ventricular cardiomyopathy (ARVC) with predominant left ventricular involvement
  • Hypertrophic cardiomyopathy (HCM) progressing to end-stage disease with impaired systolic function and/or left ventricular dilation

Penetrance

Variable; influenced by gene, age, and nongenetic factors

Prevalence of DCM

  • Estimated at 1:250 to 1:2,500
  • 20-50% of cases are familial

Inheritance

  • Familial DCM 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 DCM.
  • De novo variation may be found in children or adults.

Test Description

Clinical Sensitivity

  • 25-40% for familial DCM and 10-25% for isolated DCM 
  • Core genes for HCM and ARVC are included on this DCM panel due to gene/phenotype overlap.

Analytical Sensitivity

For massively parallel sequencing:

Variant Class Analytical Sensitivity (PPA) Estimatea (%) Analytical Sensitivity (PPA) 95% Credibility Regiona (%)

SNVs

99.2

96.9-99.4

Deletions 1-10 bp

93.8

84.3-98.2

Deletions 11-44 bp

99.9

87.8-100

Insertions 1-10 bp

94.8

86.8-98.5

Insertions 11-23 bp

99.9

62.1-100

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 diagnosis of familial dilated 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 genes
    • Regulatory region and deep intronic variants
    • Large deletions/duplications/inversions in any of the tested genes (Large deletions/duplications account for <1% of causative variants for familial DCM. )
    • Noncoding transcripts
    • The following exons are not sequenced due to technical limitations of the assay:
      • FLNC (NM_001458) exons 47, 48
      • PRKAG2 (NM_016203) exons 10, 13
      • TTN (NM_001267550) exons 172, 173, 175, 176, 177, 178, 179, 180, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 215
      • TTN (NM_133378) exons 153, 154, 155
  • 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
Gene MIM # Associated Disorder(s) Inheritance

ABCC9

601439

Cantu syndrome

Familial atrial fibrillation 12

DCM 1O

AD

ACTC1

102540

HCM 11

DCM 1R

Atrial septal defect 5

AD

ACTN2

102573

DCM 1AA with or without LVNC

AD

ALMS1

606844

Alstrom syndrome

AR

BAG3

603883

Myofibrillar myopathy 6

DCM 1HH

AD

CRYAB

123590

DCM 1II

Myofibrillar myopathy 2

AD

CSRP3

600824

HCM 12

AD

DES

125660

Myofibrillar myopathy 1

AD/AR

DCM 1I

AD

DMD

300377

Becker muscular dystrophy

Duchenne muscular dystrophy

DCM 3B

XL

DOLK

610746

Congenital disorder of glycosylation 1M

AR

DSC2

125645

ARVC 11

AD

DSG2

125671

ARVC 10

DCM 1BB

AD

DSP

125647

ARVC 8

DCM with woolly hair, keratoderma, and tooth agenesis

AD

DCM with woolly hair and keratoderma

Lethal acantholytic epidermolysis bullosa

AR

EMD

300384

Emery-Dreifuss muscular dystrophy 1

XL

FKTN

607440

DCM 1X

Muscular dystrophy-dystroglycanopathy A4 (congenital with brain and eye anomalies)

AR

FLNC

102565

Myofibrillar myopathy 5

HCM 26

Restrictive cardiomyopathy 5

Distal myopathy 4

AD

GLA

300644

Fabry disease

XL

JUP

173325

ARVC 12

AD

Naxos disease

AR

LAMP2

309060

Danon disease

XL

LDB3

605906

DCM 1C with or without LVNC

Myofibrillar myopathy 4

AD

LMNA

150330

Slovenian type heart-hand syndrome

DCM 1A

DCM with hypergonadotropic hypogonadism

Emery-Dreifuss muscular dystrophy 2

Congenital muscular dystrophy

AD

Emery-Dreifuss muscular dystrophy 3

AR

MYBPC3

600958

HCM 4

DCM 1MM

AD

MYH6

160710

DCM 1EE

Atrial septal defect 3

Sick sinus syndrome 3

AD

MYH7

160760

HCM 1

DCM 1S

AD

Myosin storage myopathy

AR

MYL2

160781

HCM 10

AD

MYL3

160790

HCM 8

AD

PKP2

602861

ARVC 9

AD

PLN

172405

HCM 18

DCM 1P

AD

PRDM16

605557

DCM 1LL

AD

PRKAG2

602743

Lethal congenital glycogen storage disease of the heart

HCM 6

Wolff-Parkinson-White syndrome

AD

RAF1

164760

Noonan syndrome 5

DCM 1NN

LEOPARD syndrome 2

AD

RBM20

613171

DCM 1DD

AD

RYR2

180902

CPVT 1

ARVC 2

AD

SCN5A

600163

Brugada syndrome 1

DCM 1E

Familial atrial fibrillation 10

Familial heart block

Familial paroxysmal ventricular fibrillation

LQTS 3

AD

Sick sinus syndrome 1

AR

SGCD

601411

DCM 1L

AD

Limb-girdle muscular dystrophy 6

AR

TAZ

300394

Barth syndrome

XL

TCAP

604488

Limb-girdle muscular dystrophy 7

AR

TMEM43

612048

Emery-Dreifuss muscular dystrophy 7

ARVC 5

AD

TNNC1

191040

HCM 13

DCM 1Z

AD

TNNI3

191044

HCM 7

Restrictive cardiomyopathy 1

DCM 1FF

AD

DCM 2A

AR

TNNT2

191045

HCM 2

Restrictive cardiomyopathy 3

DCM 1D

AD

TPM1

191010

HCM 3

DCM 1Y

AD

TTN

188840

DCM 1G

Myofibrillar myopathy 9

AD

Salih myopathy

AR

TTR

176300

Transthyretin-related amyloidosis

AD

VCL

193065

DCM 1W

AD

AD, autosomal dominant; AR, autosomal recessive; CPVT, catecholaminergic polymorphic ventricular tachycardia; LVNC, left ventricular noncompaction; XL, X-linked

References