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Laboratory for Molecular Medicine

Tests for Cardiomyopathy

The Laboratory for Molecular Medicine at Mass General Brigham Personalized Medicine offers a multitude of cardiomyopathy tests for patients.

What we offer

Included with our list of offered genetic testing is supporting documentation as well as individual details specific to ordering of a particular test.

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).

The Laboratory for Molecular Medicine at Personalized Medicine offers the following cardiomyopathy tests.

PanCardiomyopathy Panel (62 Genes) Test

The PanCardiomyopathy (PCM) Panel contains 62 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 and conventional Sanger sequencing technology.

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).

This test is used for:

  • Cases with an unclear diagnosis 
  • Diagnoses where the genetic contribution is incompletely characterized (e.g., LVNC, RCM) 
  • Comprehensive testing 

Gene Protein OMIN# 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 

The PanCardiomyopathy 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 email LMM@partners.org

 This assay is performed using Genomic DNA extracted from blood or saliva that is fragmented, adapter ligated, and barcoded. Library fragments are sequenced (2x150 base paired end) using Sequencing-By-Synthesis (SBS) chemistry and the Illumina NovaSeq sequencer with a minimum coverage of at least 20X for 90%. Sequence data are aligned to the GRCh38 assembly after discarding low quality sequences. Illumina's DRAGEN (Dynamic Read Analysis for GENomics) platform is used for demultiplexing, read mapping, genome alignment, read sorting, duplicate marking, and variant calling. Technical sensitivity of this assay is 99.10% (95% CI: 99.04-99.16%) and the positive predictive value is 99.39% (95% CI: 99.37-99.41%). 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. Variants are reported according to HGVS nomenclature. 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. There is reduced detection for larger indels, variants in low complexity regions, and variants in regions with high homology. 

 The initial sequencing component of this test is performed by the Broad Clinical Laboratory of the Broad Institute (320 Charles St, Cambridge, MA 02141; CLIA#22D2055652), and the Sanger confirmation, interpretive algorithms and clinical reports are generated by the Laboratory for Molecular Medicine at Mass General Brigham Personalized Medicine (LMM, 65 Landsdowne St, Cambridge, MA 02139; 617-768-8500; CLIA#22D1005307). This test 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.

The detection rate of the PanCardiomyopathy Panel is approximately 35% for HCM, ~37% for DCM and ~50% for ARVC. The detection rate for the other cardiomyopathies remains unknown.

Requisition form

All samples must be accompanied with a completed requisition form. Please make sure any identifiers used on the specimen are provided on the paperwork. Consent page should be signed by a health care provider. Any incomplete or missing paperwork may delay the start of testing.

Ordering

Test code: lmPCM-pnlAv6_L
Turnaround time: 6-8 weeks
Specimen required:

  • 7ml of whole blood (3-5ml for an infant) in a lavender top tube (K2EDTA or K3EDTA) OR 
  • 10 ug of DNA at a minimum concentration of 25 ng/ul (please provide DNA concentration) 

If providing DNA, please provide name and CLIA # of lab performing blood extraction.

Billing information

The Laboratory for Molecular Medicine offers several billing options for our clients and their patients; however, we do not bill insurance companies and are unable to begin testing without accurate billing information.

  • CPT code: 81439
  • Price: $1,200

Transthyretin Amyloidosis—TTR Gene Sequencing

Amyloidosis is a name given to conditions characterized by accumulation of amyloid (proteinaceous deposits) in various tissues. In transthyretin (TTR) amyloidosis, the most common hereditary form of amyloidosis, the amyloid material is TTR.  

TTR gene sequencing should be ordered for individuals with a clear or suspected diagnosis of TTR amyloidosis. 

The most common presentation of transthyretin amyloidosis is neuropathic, which typically manifests as autonomic or sensory motor impairment. Cardiac involvement is frequent in transthyretin amyloidosis is frequent and most often takes the form of restrictive cardiomyopathy. The enlarged appearance of the interventricular septum and left ventricular muscle reflects the deposition of TTR in these structures rather than true hypertrophy. The symmetrical pattern of enlargement and histological appearance help differentiate this condition from other forms of hypertrophic cardiomyopathy. Additional cardiac symptoms can include arrhythmias, congestive heart failure and sudden death. Variants in TTR are a primary cause of transthyretin amyloidosis and the disease has a high prevalence in certain ethnic groups, such as African Americans. 

Gene Protein OMIN# Locus
TTR Transthyretin 176300 18q12.1

This test is performed by Sanger sequencing of the coding regions and splice sites of the listed gene. This test does not detect large deletions or variants in non-coding regions that could affect gene expression. 

This test is greater than 99.9% accurate in detecting variants in the sequence analyzed. 

Sequencing of TTR detected more than 99% of disease-causing variant for transthyretin amyloidosis (GeneReviews). Learn more about transthyretin amyloidosis.

Requisition form

All samples must be accompanied with a completed requisition form. Please make sure any identifiers used on the specimen are provided on the paperwork. Consent page should be signed by a health care provider. Any incomplete or missing paperwork may delay the start of testing.

Ordering

Test code: lmTTR-av2_L
Turnaround time: 3 weeks
Specimen required:

  • 4-8ml of whole blood (3-5ml for an infant) in a lavender top tube (K2EDTA or K3EDTA) or
  • 10 ug of DNA at a minimum concentration of 25 ng/ul (please provide DNA concentration)

If providing DNA, please provide name and CLIA # of lab performing blood extraction.

Billing information 

The Laboratory for Molecular Medicine offers several billing options for our clients and their patients; however, we do not bill insurance companies and are unable to begin testing without accurate billing information.

  • CPT code: 81404
  • Price: $600