Diagnostics

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Pan Cardiomyopathy Panel

The Pan Cardiomyopathy Panel is a comprehensive NGS panel that can be used to confirm a clinical diagnosis of cardiomyopathy or identify at-risk individuals. Cardiomyopathy is a disease of the heart muscle that can cause the heart to become weak, rigid, enlarged, or thickened. Cardiomyopathy can lead to irregular heart beats, progressive heart failure, or sudden cardiac death. There are many forms of cardiomyopathy, some of which are acquired and some of which are inherited. The most common hereditary cardiomyopathies include hypertrophic cardiomyopathy, dilated cardiomyopathy, left ventricular noncompaction, arrhythmogenic right ventricular cardiomyopathy, and restrictive cardiomyopathy. The disorders show significant clinical overlap, and demonstrate allelic and locus heterogeneity.

Prevalence

The prevalence of the various forms of cardiomyopathy are:

  • Hypertrophic cardiomyopathy- 1/200 to 1/500 (Semsarian et al, 2015)
  • Dilated cardiomyopathy- 1/2,700 (Codd et al, 1989)
  • Left ventricular noncompaction- 1/500 to 1/2,000 (Ronderos et al, 2016)
  • Arrhythmogenic right ventricular cardiomyopathy – 1/1000 to 1/1,250 (Peters, 2006)
  • Restrictive cardiomyopathy – Unknown (rare)

Included Disorders

This panel includes genes associated with:

  • Hypertrophic cardiomyopathy
  • Dilated cardiomyopathy
  • Left ventricular noncompaction
  • Arrhythmogenic right ventricular cardiomyopathy
  • Restrictive cardiomyopathy
  • Danon disease
  • Fabry disease
  • Myofibrillar myopathy
  • Timothy syndrome
  • Transthyretin (TTR) amyloidosis
  • Wolff-Parkinson-White syndrome
  • Barth syndrome
  • Duchenne and Becker muscular dystrophy
  • Emery-Dreifuss muscular dystrophy
  • Other disorders

Inheritance and Penetrance

Cardiomyopathies are typically inherited in an autosomal dominant manner, although some of the conditions on the panel are inherited in an autosomal recessive or X-linked manner.

Autosomal Recessive:

  • Pompe disease
  • Naxos syndrome
  • Primary carnitine deficiency
  • Glycogen storage disease type IIIa/b
  • FKTN and FKRP muscular dystrophy-dystroglycanophathies
  • Emery-Dreifuss muscular dystrophy

X-linked:

  • Barth syndrome
  • Danon disease
  • Duchenne muscular dystrophy
  • Emery-Dreifuss muscular dystrophy
  • Fabry disease

Hereditary cardiomyopathies typically demonstrate reduced and age-related penetrance, and often show significant intra- and inter- family variability.

 

Clinical Sensitivity

The clinical sensitivity of this test is dependent on the patient’s phenotype. In general, the clinical sensitivity for each condition is listed below:

  • Hypertrophic cardiomyopathy- 60% (Gersh et al, 2011)
  • Dilated cardiomyopathy- 40% (Hershberger et al, 2013)
  • Left ventricular noncompaction- 20-40% (Klaassen et al, 2008; Hoedemaekers et al, 2010)
  • Arrhythmogenic right ventricular cardiomyopathy- 50% (Quarta et al, 2011)
  • Restrictive cardiomyopathy- ~35% (Teekakirikul et al, 2013)

Methodology and Analytical Sensitivity

Next-generation sequencing technology is used to test clinically relevant portions of each gene, including coding exons, adjacent flanking bases, and selected introns/noncoding variants. Pathogenic and likely pathogenic variants are confirmed by orthogonal methods. Copy number variants, including intragenic deletions and duplications are detected to a resolution of a single exon. To request analysis of a specific single exon copy number variant, please contact our Client Services team prior to ordering. Analytical sensitivity and specificity of the assay is 99.5%.

Indications for Testing

  • Confirmation of a clinical diagnosis
  • Unexplained cardiac arrest
  • Unexplained cardiomyopathy
  • Risk assessment for asymptomatic family of members of proband with molecular diagnosis of cardiomyopathy

Included Genes (52)

 

ABCC9 CSRP3 EYA4 JUP PKP2 SLC22A5 TPM1
ACTC1 DES FHL1 LAMP2 PLN TAZ TTN
ACTN2 DMD FKRP LDB3 PRKAG2 TCAP TTR
AGL DOLK FKTN LMNA RAF1 TGFB3 VCL
BAG3 DSC2 FLNC MYBPC3 RBM20 TMEM43
CACNA1C DSG2 GAA MYH7 RYR2 TNNC1
CAV3 DSP GLA MYL2 SCN5A TNNI3
CRYAB EMD HCN4 MYL3 SGCD TNNT2

Optional Additions to Pan Cardiomyopathy Panel

Emerging Evidence Genes

Emerging evidence genes can also be added on to the Pan Cardiomyopathy Panel. These genes do not have a clear association with hereditary cardiomyopathy, but emerging evidence suggests that they may play a role in disease.

ANKRD1 GATAD1 MYPN
CAL3 ILK NEBL
CHRM2 JPH2 NEXN
CTF1 LAMA4 NKX2-5
CTNNA3 LRRC10 NPPA
DTNA MYH6 PDLIM3
FHL2 MYLK2 PLEKHM2
GATA4 MYOM1 TMPO
GATA6 MYOZ2 TXNRD2

 

RASopathies Add-On Panel (17)

Genes associated with the “RASopathy” spectrum of disorders, which frequently include cardiomyopathy as a symptom, may be added onto the Pan Cardiomyopathy panel (RAF1, a RASopathy gene, is already included in the comprehensive panel).

Mutations in genes related to the Ras/MapK cell signaling pathway cause a group of related disorders known as the “RASopathies.” These disorders include Noonan syndrome, cardiofaciocutaneous syndrome, Costello syndrome, neurofibromatosis, LEOPARD syndrome, and Legius syndrome, among others. The Ras/MapK pathway is involved in cell growth, differentiation, proliferation, and death. The Ras/MAPK spectrum of disorders shows both genetic and allelic heterogeneity, meaning that different mutations in the same gene can cause different phenotypes, and mutations in different genes can cause the same phenotype. Although the specific phenotype varies by disease, many, but not all, of these disorders include hypertrophic cardiomyopathy as a feature.

A2ML1 MAP2K2 RRAS
BRAF NF1 SHOC2
CBL NRAS SOS1
HRAS PTPN11 SOS2
KRAS RASA1 SPRED1
MAP2K1 RIT1

Syndromic Pediatric Add-On Panel (8)

Genes associated with pediatric onset, syndromic, autosomal recessive disorders with cardiomyopathy as feature can also be added to the Pan Cardiomyopathy Panel.

ACADVL ELAC2
ALMS1 MTO1
CPT2 SDHA
DNAJC19 TMEM70

References

  1. Codd MB, Sugrue DD, Gersh BJ, Melton LJ 3rd. Epidemiology of idiopathic dilated and hypertrophic cardiomyopathy. A population-based study in Olmsted County, Minnesota, 1975-1984. Circulation. 1989;80:564–72.
  2. Gersh BJ, Maron BJ, Bonow RO, et al. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2011;124(24):2761-96.
  3. Hershberger RE, Hedges DJ, Morales A. Dilated cardiomyopathy: the complexity of a diverse genetic architecture. Nat Rev Cardiol. 2013;10:531–47.
  4. Hoedemaekers YM, Caliskan K, Michels M, et al. The importance of genetic counseling, DNA diagnostics, and cardiologic family screening in left ventricular noncompaction cardiomyopathy. Circ Cardiovasc Genet. 2010;3(3):232-9.
  5. Klaassen S, Probst S, Oechslin E, et al. Mutations in sarcomere protein genes in left ventricular noncompaction. Circulation. 2008;117(22):2893-901.
  6. Quarta G, Muir A, Pantazis A, et al. Familial evaluation in arrhythmogenic right ventricular cardiomyopathy: impact of genetics and revised task force criteria. Circulation. 2011;123(23):2701-9.
  7. Ronderos R, Avegliano G, Borelli E, Kuschnir P, Castro F, Sanchez G, Perea G, Corneli M, Zanier MM, Andres S, Aranda A, Conde D, Trivi M, Estimation of Prevalence of the Left Ventricular Non Compaction Among Adults, The American Journal of Cardiology (2016), doi: 10.1016/ j.amjcard.2016.06.033.
  8. Semsarian C, Ingles J, Maron MS, Maron BJ. New perspectives on the prevalence of hypertrophic cardiomyopathy. J Am Coll Cardiol. 2015;65(12):1249-54.
  9. Teekakirikul P, Kelly MA, Rehm HL, Lakdawala NK, Funke BH. Inherited cardiomyopathies: molecular genetics and clinical genetic testing in the postgenomic era. J Mol Diagn. 2013;15(2):158-70.