Pan Cardiomyopathy Panel

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Genes: 51 genes

Methodology: A combination of next generation sequencing technology and Sanger sequencing

Analytical Sensitivity:

Substitutions: 100% (95%CI=98.5-100)

Small InDels: 95% (95%CI=83-99)

Clinical Sensitivity: See below.

Additional Links:

The Pan Cardiomyopathy (PCM) Panel contains 51 cardiomyopathy genes including Titin (TTN), which encodes the largest human protein. This panel covers genes associated with HCM, DCM, RCM, LVNC, ARVC and CPVT and uses a combination of Next Generation Sequencing technology and conventional Sanger sequencing.

For illustrative reference, click to see one of our images or diagrams. Genes on Pan Cardiomyopathy Panels, Disease-Gene Associations, Gene Cellular Location.

Please select on the disease to read more: HCM, DCM, ARVC/CPVT, or LVNC.

 

Current Tests:

Pan Cardiomyopathy Panel - 51 genes

  • HCM Panel - 18 genes§
  • DCM Panel - 27 genes§
  • ARVC/CPVT Panel - 8 genes§
  • LVNC Panel - 10 genes§

        §Optional reflex to remaining genes

Storage Cardiomyopathy - please select a disease to learn more

For any other single gene tests, please call the LMM at 617-768-8499 or lmm@partners.org.

 

When to order which panel?

The Pan Cardiomyopathy panel may shorten the “testing odyssey” when a clear diagnosis has not been established. However, because many genes have not yet been associated with more than one cardiomyopathy, interpretation of novel variants may be more difficult when they are found in a gene that is not (yet) known to cause the patient’s cardiomyopathy. Please note: We are expecting an increase in “variants of unknown significance” and recommend careful consideration of the following factors when deciding whether to order the full panel or the disease specific sub-panels. The Pan Cardiomyopathy Panel may be best suited for patients who have already exhausted current testing options or whose clinical diagnosis is not yet clear. It may also be a good first line test for patients who have a family history where the number of living affected relatives would allow segregation analysis to establish or rule out pathogenicity for “variants of unknown significance (VUSs)”. Finally, the patient’s personal preferences should be considered as VUSs can cause anxiety.


  


 

Adapted with permission from the American Society for Clinical Investigation; Morita et al (2005). American Society for Clinical Investigation.
Journal of Clinical Investigation 2005 March 1.

Methodology

This test is performed by oligonucleotide-based target capture (Sureselect, Agilent) followed by next generation sequencing (Illumina HiSeq2000). Sanger sequencing is used to provide data for bases with insufficient coverage. Variant calls are generated using the Burrows-Wheeler Aligner (bwa) followed by GATK analysis. 

 

Analytical Sensitivity

Analytical sensitivity (the ability to accurately detect variants that are known to be present) was established by sequencing 73 samples that contained a large number of previously characterized sequence variants. The Pan Cardiomyopathy panel as well as the disease specific panels include a Next Generation sequencing (NGS) assay followed by Sanger sequencing of regions that cannot be reliably covered by the NGS part of the test. This combination of technologies detected all substitution variants (single base changes) and 95% of small insertions or deletions (InDels). See the table below for details.

      PAN CARDIO PANEL
 VARIANT TYPE  #  FN SENSITIVITY 95% CI
Substitutions 258 0 100 98.5 - 100
InDels (all) 39 2 94.9 83.1 - 98.6
>10 bp 8 1 87.5 52.9 - 97.8
3-5 bp 13 1 92.3 66.7 - 98.6
1-2 bp 18 0 100 82.4 - 100

 

Clinical Sensitivity

Our test was clinically validated using 73 anonymized samples where previous testing had not identified a clinically significant variant. Preliminary analysis of the variants detected suggests that the detection rate of the Pan Cardiomyopathy Panel will likely be >33-38% for DCM. The detection rate for the other cardiomyopathies remains unknown at this point but will be equal or greater than the sensitivity of the tests it replaces (HCM: ~52%; ARVC: ~50%). The clinical sensitivity of the disease specific sub-panels is not known at this point.


Disease Backgrounds

Hypertrophic cardiomyopathy (HCM) is characterized by unexplained left ventricular hypertrophy (LVH) in a non-dilated ventricle. With a prevalence estimated to be ~1/500 in the general population, HCM is the most common monogenic cardiac disorder. To date, over 1000 variants have been identified in genes causative of HCM, most of which affect the sarcomere, the contractile unit of the cardiac muscle. In addition, defects in genes involved in storage diseases, such as LAMP2, PRKAG2 and GLA, typically cause systemic disease but may also result in predominant cardiac manifestations, which can mimic hypertrophic cardiomyopathy (HCM). For additional information about HCM, please visit GeneReviews.

 

Dilated cardiomyopathy (DCM) is characterized by ventricular chamber enlargement and systolic dysfunction with normal left ventricular wall thickness. The estimated prevalence of DCM is 1/2,500 and about 20-35% of cases have a family history showing a predominantly autosomal mode of inheritance. To date, over 40 genes have been demonstrated to cause DCM, encoding proteins involved in the sarcomere, Z-disk, nuclear lamina, intermediate filaments and the dystrophin-associated glycoprotein complex. Variants in some genes cause additional abnormalities: LMNA variants are frequently found in DCM that occurs with progressive conduction system disease. Variants in the TAZ gene cause Barth syndrome, an X-linked cardioskeletal myopathy in infants. In addition, variants in several genes (including LMNA, DES, SGCD, TCAP and EMD) can cause DCM in conjunction with skeletal myopathy.  For additional information about DCM, please visit GeneReviews

 

Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is estimated to affect approximately 1/5,000 individuals in the general population, about half of which have a family history. The disease is characterized by replacement of myocytes by fatty or fibrofatty tissue, mainly in the right ventricle. The resulting manifestations are broad and include ventricular tachyarrhythmias and sudden death in young individuals and athletes. ARVC is typically inherited in an autosomal dominant fashion with incomplete penetrance and variable expressivity and to date, 5 ARVC genes (DSP, DSC2, DSG2, PKP2, TMEM43) have been identified, all but one (TMEM43) encode components of the desmosome. For more information about ARVC, please visit GeneReviews.

 

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is typically characterized by exercise induced syncope due to ventricular tachycardia in individuals without structural heart disease. Two CPVT genes are known to date (RYR2 – autosomal dominant; CASQ2 – autosomal recessive). For more information about CPVT, please visit GeneReviews.

 

Left ventricular noncompaction (LVNC) has recently been established as a specific type of cardiomyopathy and is characterized by a spongy appearance of the left ventricular myocardium, resulting from an arrest in normal cardiac development. LVNC can be found in isolation or in association with other cardiomyopathies (HCM, DCM) as well as congenital cardiac abnormalities. The population prevalence is not known but LVNC is reported in ~0.014% of echocardiograms. LVNC is often familial and the genetic spectrum is beginning to emerge although it is not yet well defined. LVNC genes reported to date include ACTC, DTNA, LDB3, MYBPC3, MYH7, TAZ, and TNNT2 (Montserrat 2007, Klaassen 2008; Kaneda 2007, Zaragoza 2007; reviewed in: Maron 2006, Finsterer 2009). For more information about LVNC, please visit OMIM.org.


For any additional information, please contact us at 617-768-8500 or lmm@partners.org.

Last revised: July 14, 2011