Pan Cardiomyopathy Panel (62 Genes) Test Details
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Background
Inherited cardiomyopathies are a group of genetically heterogeneous cardiac diseases with a relatively high population frequency, association with sudden cardiac death, and substantial genetic component. Familial inheritance is common and typically follows an autosomal dominant pattern, though all other forms of inheritance exist. The predominant forms are hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM), followed by arrhythmogenic cardiomyopathy and left ventricular non-compaction (LVNC).
Read More...Available Cardiomyopathy Panel Tests
- For cases with an unclear diagnosis
- For diagnoses where the genetic contribution is incompletely characterized (e.g. LVNC, RCM)
- For comprehensive testing
Storage Cardiomyopathy
Gene Information
Read More for expanded gene table.
Read More...Gene | Protein | OMIM# | Locus |
ABCC9 | ATP-Binding Cassette, Subfamily C, Member 9 | 601439 | 12p12.1 |
ACTC1 | Actin, Alpha, Cardiac Muscle | 102540 | 15q14 |
ACTN2 | Actinin, Alpha-2 | 102573 | 1q42-q43 |
ANKRD1 | Ankyrin Repeat Domain-Containing Protein 1 | 609599 | 10q23.3 |
BAG3 | BCL2-Associated Athanogene 3 | 603883 | 10q25.2-q26.2 |
CASQ2 | Calsequestrin 2 | 114251 | 1p13.1 |
CAV3 | Caveolin 3 | 601253 | 3p25.3 |
CHRM2 | Cholinergic Receptor, Muscarinic, 2 | 118493 | 7q33 |
CRYAB | Crystallin, Alpha-B | 123590 | 11q23.1 |
CSRP3 | Cysteine- And Glycine-Rich Protein 3 | 600824 | 11p15.1 |
DES | Desmin | 125660 | 2q35 |
DMD | Dystrophin | 300377 | Xq21.2-p21.1 |
DOLK | Dolichol Kinase | 610746 | 9q34.11 |
DSC2 | Desmocollin 2 | 600271 | 18q12.1 |
DSG2 | Desmoglein 2 | 125671 | 18q12.1 |
DSP | Desmoplakin | 125485 | 4q21.3 |
DTNA | Dystrobrevin, Alpha | 601239 | 18q12.1 |
EMD | Emerin | 300384 | Xq28 |
FHL2 | Four-and-a-half LIM Domains 2 | 602633 | 2q12.2 |
GATAD1 | Gata Zinc Finger Domain-Containing Protein 1 | 614518 | 7q21-q22 |
GLA | Galactosidase, Alpha | 300644 | Xq22 |
ILK | Integrin-Linked Kinase | 602366 | 11p15.4 |
JPH2 | Junctophilin 2 | 605267 | 20q13.12 |
JUP | Junction Plakoglobin | 173325 | 17q21 |
LAMA4 | Laminin, Alpha-4 | 600133 | 6q21 |
LAMP2 | Lysosome-Associated Membrane Protein 2 | 309060 | Xq24 |
LDB3 | Lim Domain-Binding 3 | 605906 | 10q22.3-q23.2 |
LMNA | Lamin A/C | 150330 | 1q22 |
MURC | Muscle Related Coiled-Coil Protein | n/a | 9q31.1 |
MYBPC3 | Myosin-Binding Protein C, Cardiac | 600958 | 11p11.2 |
MYH6 | Myosin, Heavy Chain 6, Cardiac Muscle, Alpha | 160710 | 14q12 |
MYH7 | Myosin, Heavy Chain 7, Cardiac Muscle, Beta | 160760 | 14q12 |
MYL2 | Myosin, Light Chain 2, Regulatory, Cardiac, Slow | 160781 | 12q24.11 |
MYL3 | Myosin, Light Chain 3, Alkali, Ventricular, Skeletal, Slow | 160790 | 3p21.3-p21.2 |
MYLK2 | Myosin Light Chain Kinase 2 | 606566 | 20q13.31 |
MYOM1 | Myomesin 1 | 603508 | 18p11.31 |
MYOZ2 | Myozenin 2 | 605602 | 4q26-q27 |
MYPN | Myopalladin | 608517 | 10q21.3 |
NEBL | Nebulette | 605491 | 10p12 |
NEXN | Nexilin (F Actin Binding Protein) | 613121 | 1p31.1 |
PDLIM3 | PDZ And LIM Domain Protein 3 | 605899 | 4q35.1 |
PKP2 | Plakophilin 2 | 602861 | 12p11 |
PLN | Phospholamban | 172405 | 6q22.1 |
PRDM16 | PR Domain-Containing Protein 16 | 605557 | 1p36.32 |
PRKAG2 | Protein Kinase, AMP-Activated, Noncatalytic, Gamma-2 | 602743 | 7q36.1 |
PTPN11 | Protein-Tyrosine Phosphatase, Nonreceptor-Type, 11 | 176876 | 12q24.13 |
RAF1 | V-RAF-1 Murine Leukemia Viral Oncogene Homolog 1 | 164760 | 3p25.2 |
RBM20 | RNA-Binding Motif Protein 20 | 613171 | 10q25.2 |
RYR2 | Ryanodine Receptor 2 (Cardiac) | 180902 | 1q43 |
SCN5A | Sodium Channel, Voltage-Gated, Type V, Alpha Subunit | 600163 | 3p21 |
SGCD | Sarcoglycan, Delta (35Kda Dystrophin-Associated Glycoprotein) | 601411 | 5q33-q34 |
TAZ | Tafazzin | 300394 | Xq28 |
TCAP | Titin-Cap (Telethonin) | 604488 | 17q12 |
TMEM43 | Transmembrane Protein 43 | 612048 | 3p25.1 |
TNNC1 | Troponin C Type 1 (Slow) | 191040 | 3p21.1 |
TNNI3 | Troponin I Type 3 (Cardiac) | 191044 | 19q13.4 |
TNNT2 | Troponin T Type 2 (Cardiac) | 191045 | 1q32 |
TPM1 | Tropomyosin 1 (Alpha) | 191010 | 15q22.1 |
TRDN | Triadin | 603283 | 6q22.31 |
TTN | Titin | 188840 | 2q31 |
TTR | Transthyretin | 176300 | 18q12.1 |
VCL | Vinculin | 193065 | 10q22.2 |
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Methodology
The Pan Cardiomyopathy Panel includes 62 genes: ABCC9, ACTC1, ACTN2, ANKRD1, BAG3, CASQ2, CAV3, CHRM2, CRYAB, CSRP3, DES, DMD, DOLK, DSC2, DSG2, DSP, DTNA, EMD, FHL2, GATAD1, GLA (includes deep intronic c.639+919G>A variant), ILK, JPH2, JUP, LAMA4 (excludes exon 2A* in NM_001105209.1 and exon 8 in NM_002290.3), LAMP2, LDB3, LMNA (excludes exons 1B* and 13B* in NM_001257374.2), CAVIN4, MYBPC3 (includes the intronic c.1224-52G>A variant), MYH6 (excludes exon 37 in NM_002471.3), MYH7, MYL2, MYL3, MYLK2, MYOM1, MYOZ2, MYPN, NEBL, NEXN, PDLIM3, PKP2, PLN, PRDM16, PRKAG2, PTPN11, RAF1, RBM20, RYR2, SCN5A, SGCD, TAZ, TCAP, TMEM43, TNNC1, TNNI3, TNNT2, TPM1, TRDN, TTN, TTR, VCL. *Exon from an alternate transcript. For additional information on reference sequences and exon coverage, please click here.
Read More...This assay is performed using the PerkinElmer Sciclone® G3 Workstation combined with the Agilent SureSelect Clinical Research Exome capture kit (#G9496A 5190-7344; targeting coding regions (exons) and canonical splice sites) followed by sequencing on the Illumina NextSeq 550 (High-Output v2 kit). Reads are aligned to the GRCh37 reference sequence using the Burrows-Wheeler Aligner (BWA 0.7.17), and variant calls are made using the Genomic Analysis Tool Kit (GATK v4.0.3.0). Detection of copy number variants (CNVs) encompassing 2 or more exons is performed using next-generation sequencing read data and the VisCap algorithm. CNV analysis is only performed when data meets necessary quality standards and may not be available for all cases. Variant calls are limited bioinformatically to the associated region of interest for the assay (see above for details). Sanger sequencing is used for fill in when bases have <12x coverage. All clinically significant variants are confirmed by Sanger sequencing or droplet digital PCR; variants classified as likely benign or benign are not confirmed.
Variant classifications are based on ACMG/AMP criteria (Richards et al. 2015) with ClinGen rule specifications (https://www.clinicalgenome.org/working-groups/sequence-variant-interpretation/). Variants are reported according to HGVS nomenclature (www.hgvs.org/mutnomen). Likely benign and benign variants are not included in this report but are available upon request.
This test does not routinely detect variants in non-coding regions (aside from the canonical splice sites), triplet repeat expansions, translocations, inversions, and copy number variants encompassing less than 2 consecutive exons. There is reduced detection for larger indels, variants in low complexity regions, and variants in regions with high homology.
This test was developed, and its performance characteristics determined by the Laboratory for Molecular Medicine at Partners HealthCare Personalized Medicine (LMM, 65 Landsdowne St, Cambridge, MA 02139; 617-768-8500; CLIA#22D1005307). It has not been cleared or approved by the U.S. Food and Drug Administration (FDA). The FDA has determined that such clearance or approval is not necessary.
LessAnalytical and Clinical Sensitivity
This test is 99.93% sensitive (95% CI =99.92-99.94%) to detect variants changing a single base and 96.75% sensitive to detect insertion/deletions (95% CI =96.28-97.22%) within covered regions. Technical positive predictive value for single nucleotide variant changes is 99.42% (95% CI = 99.37-99.48%) and 94.16% (95% CI = 93.34-94.97%) for insertion/deletion changes within covered regions. There is demonstrated reduced detection for larger indels, especially in low complexity regions with corresponding low sequence coverage and in regions with high homology.
The detection rate of the Pan Cardiomyopathy Panel is approximately 35% for HCM, ~37% for DCM and ~50% for ARVC. The detection rate for the other cardiomyopathies remains unknown.