Cardiac Disease

Genomics and Pathology Services (GPS) offers germline variant detection by next-generation sequencing in key genes implicated in a variety of arrhythmias and cardiomyopathies.

Results can provide physicians with useful information to solidify a diagnosis, allowing for more appropriate patient management and surveillance. They also enable tailored genetic counseling in both the patient and at-risk family members.

REQUISITIONGENES


Indications for Testing

Indications for testing include symptoms of a variety of arrhythmias and cardiomyopathies such as Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), long QT syndrome (LQTS), arrhythmogenic right ventricular cardiomyopathy (ARVC), dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), Noonan syndrome and  thoracic aneurysm and aortic dissection.


Available Tests and Gene Lists

Testing is performed by exome capture of the coding regions of relevant genes followed by next generation sequencing to detect small sequence variants. Starred tests (*) include additional testing for deletions and duplications by an alternate methodology (aCGH) when sequencing does not identify genetic variation consistent with a molecular diagnosis. Core gene panels are comprised of genes established as causal for the relevant clinical condition. Expanded gene panels include all genes found in the core panel plus additional genes of uncertain significance that are implicated as candidate genes for the condition.

***Please note that when a CORE panel is ordered, only the core panel genes will be analyzed and reported. When an EXPANDED panel is ordered, the core panel genes will be analyzed first for clinically significant variation. If no molecular diagnosis is made, the analysis will then extend to the expanded gene set, which includes genes of uncertain significance that have been implicated in the relevant conditions.

*Cardiac Diseases Gene panel

CORE: 82 genes sequenced: ACADVL, ACTA2, ACTC1, ACTN2, AGL, ALMS1, ALPK3, BAG3, BGN, CACNA1C, CALM1, CALM2, CALM3, CASQ2, COL3A1, COL5A2, CPT2, CRYAB, CSRP3, DES, DMD, DNAJC19, DOLK, DSC2, DSG2, DSP, EFEMP2, ELAC2, EMD, FBN1, FBN2, FHL1, FKRP, FKTN, FLNC, FOXE3, GAA, GLA, JPH2, JUP, KCNE1, KCNH2, KCNJ2, KCNQ1, LAMP2, LMNA, LOX, MFAP5, MTO1, MYBPC3, MYH7, MYH11, MYL2, MYL3, MYLK, NEXN, PKP2, PLN, PRKAG2, PRKG1, RBM20, RYR2, SCN5A, SDHA, SGCD, SCL25A4, SMAD2, SMAD3, TAZ, TECRL, TGFB2, TGFBR1, TGFBR2, TMEM43, TNNC1, TNNI3, TNNT2, TPM1, TRDN, TTN, TTR and VCL.

EXPANDED: 150 genes sequenced: ABCC9, ACADVL, ACTA2, ACTC1, ACTN2, AGL, AKAP9, ALMS1, ALPK3, ANKRD1, BAG3, BGN, CACNA1C, CACNA2D1, CACNB2, CALM1, CALM2, CALM3, CALR3, CASQ2, CAV3, CDH2, CHRM2, COL3A1, COL5A2, COL9A1, CPT2, CRYAB, CSRP3, CTF1, DES, DMD, DNAJC19, DOLK, DSC2, DSG2, DSP, DTNA, EFEMP2, ELAC2, EMD, EYA4, FBN1, FBN2, FHL1, FKRP, FKTN, FLNA, FLNC, FOXE3, GAA, GATA4, GATA6, GATAD1, GLA, GPD1L, HAND1, HCN4, ILK, JPH2, JUP, KCND3, KCNE1, KCNE2, KCNE3, KCNE5, KCNH2, KCNJ2, KCNJ5, KCNJ8, KCNQ1, KLF10, LAMA4, LAMP2, LDB3, LMNA, LOX, MAT2A, MFAP5, MIB1, MTO1, MYBPC3, MYH6, MYH7, MYH11, MYL2, MYL3, MYLK, MYLK2, MYLK3, MYOM1, MYOZ2, MYPN, NEBL, NEXN, NKX2-5, NOTCH1, NRAP, OBSCN, PDLIM3, PKP2, PLEKHM2, PLN, PPCS, PRDM16, PRKAG2, PRKG1, PSEN2, RAF1, RANGRF, RBM20, RYR2, SCN1B, SCN2B, SCN3B, SCN4B, SCN5A, SCN10A, SDHA, SGCD, SLC2A10, SLC25A4, SLMAP, SMAD2, SMAD3, SNTA1, TAZ, TBX20, TCAP, TECRL, TGFB2, TGFB3, TGFBR1, TGFBR2, TJP1, TMEM43, TNNC1, TNNI3, TNNI3K, TNNT2, TPM1, TRDN, TRIM63, TRPM4, TTN, TTR, TXNRD2, VCL, YWHAE and ZBTB17.

*Arrhythmia panel

CORE: 13 genes sequenced:CACNA1C, CALM1, CALM2, CALM3, CASQ2, KCNE1, KCNH2, KCNJ2, KCNQ1, RYR2, SCN5A, TECRL and TRDN.

EXPANDED: 35 genes sequenced: AKAP9, CACNA1C, CACNA2D1, CACNB2, CALM1, CALM2, CALM3, CASQ2, CAV3, GPD1L, HCN4, KCND3, KCNE1, KCNE2, KCNE3, KCNE5, KCNH2, KCNJ2, KCNJ5, KCNJ8, KCNQ1, PKP2, RANGRF, RYR2, SCN1B, SCN2B, SCN3B, SCN4B, SCN5A, SCN10A, SLMAP, SNTA1, TECRL, TRDN and TRPM4.

Brugada Syndromes panel

CORE: 1 gene sequenced: SCN5A

EXPANDED: 17 genes sequenced: CACNA2D1, CACNB2, GPD1L, HCN4, KCND3, KCNE3, KCNE5, KCNJ8, PKP2, RANGRF, SCN1B, SCN2B, SCN3B, SCN5A, SCN10A, SLMAP and TRPM4.

*Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) panel

CORE: 7 genes sequenced: CALM1, CALM2, CALM3, CASQ2, RYR2, TECRL and TRDN.

*Long QT Syndromes panel

CORE: 10 genes sequenced:  CACNA1C, CALM1, CALM2, CALM3, KCNE1, KCNH2, KCNJ2, KCNQ1, SCN5A, and TRDN.

EXPANDED: 16 genes sequenced:  AKAP9, CACNA1C, CALM1, CALM2, CALM3, CAV3, KCNE1, KCNE2, KCNH2, KCNJ2, KCNJ5, KCNQ1, SCN4B, SCN5A, SNTA1 and TRDN.

*Cardiomyopathy panel

CORE: 52 genes sequenced: ACADVL, ACTC1, ACTN2, AGL, ALMS1, ALPK3, BAG3, CPT2, CRYAB, CSRP3, DES, DMD, DNAJC19, DOLK, DSC2, DSG2, DSP, ELAC2, EMD, FHL1, FKRP, FKTN, FLNC, GAA, GLA, JPH2, JUP, LAMP2, LMNA, MTO1, MYBPC3, MYH7, MYL2, MYL3, NEXN, PKP2, PLN, PRKAG2, RBM20, SCN5A, SDHA, SGCD, SLC25A4, TAZ, TMEM43, TNNC1, TNNI3, TNNT2, TPM1, TTN, TTR and VCL. 

EXPANDED: 96 genes sequenced: ABCC9, ACADVL, ACTC1, ACTN2, AGL, ALMS1, ALPK3, ANKRD1, BAG3, CALR3, CAV3, CDH2, CHRM2, CPT2, CRYAB, CSRP3, CTF1, DES, DMD, DNAJC19, DOLK, DSC2, DSG2, DSP, DTNA, ELAC2, EMD, EYA4, FHL1, FKRP, FKTN, FLNC, GAA, GATA4, GATA6, GATAD1, GLA, HAND1, ILK, JPH2, JUP, KLF10, LAMA4, LAMP2, LDB3, LMNA, MIB1, MTO1, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYLK2, MYLK3, MYOM1, MYOZ2, MYPN, NEBL, NKX2-5, NEXN, NRAP, OBSCN, PDLIM3, PKP2, PLEKHM2, PLN, PPCS, PRDM16, PRKAG2, PSEN2, RAF1, RBM20, RYR2, SCN5A, SDHA, SGCD, SLC25A4, TAZ, TBX20, TCAP, TGFB3, TJP1, TMEM43, TNNC1, TNNI3, TNNI3K, TNNT2, TPM1, TRIM63, TTN, TTR, TXNRD2, YWHAE, VCL and ZBTB17. 

*Arrhythmogenic Right Ventricular Cardiomyopathy panel

CORE: 11 genes sequenced: DES, DSC2, DSG2, DSP, JUP, LMNA, PKP2, PLN, SCN5A, TMEM43 and TTN.

EXPANDED: 17 genes sequenced: CDH2, DES, DSC2, DSG2, DSP, JUP, LMNA, MYBPC3, MYH7, MYL3, PKP2, PLN, SCN5A, TGFB3, TJP1, TMEM43 and TTN.

*Dilated Cardiomyopathy panel

CORE: 33 genes sequenced: ACADVL, ACTC1, ACTN2, ALMS1, BAG3, CPT2, CRYAB, DES, DMD, DNAJC19, DOLK, DSP, EMD, FKRP, FKTN, FLNC, JPH2, LAMP2, LMNA, MYH7, NEXN, PLN, RBM20, SCN5A, SDHA, SGCD, TAZ, TNNC1, TNNI3, TNNT2, TPM1, TTN and VCL.

EXPANDED: 68 genes sequenced: ABCC9, ACADVL, ACTC1, ACTN2, ALMS1, ANKRD1, BAG3, CHRM2, CPT2, CRYAB, CTF1, DES, DMD, DNAJC19, DOLK, DSC2, DSG2, DSP, DTNA, EMD, EYA4, FKRP, FKTN, FLNC, GATA4, GATA6, GATAD1, HAND1, ILK, JPH2, LAMA4, LAMP2, LDB3, LMNA, MIB1, MYH6, MYH7, MYLK3, MYPN, NEBL, NEXN, NKX2-5, NRAP, OBSCN, PLEKHM2, PLN, PPCS, PRDM16, PSEN2, RAF1, RBM20, RYR2, SCN5A, SDHA, SGCD, TAZ, TBX20, TCAP, TNNC1, TNNI3, TNNI3K, TNNT2, TPM1, TTN, TXNRD2, VCL, YWHAE and ZBTB17.

Hypertrophic Cardiomyopathy panel

CORE: 28 genes sequenced: ACADVL, ACTC1, ACTN2, AGL, ALPK3, BAG3, CSRP3, DES, ELAC2, FHL1, FLNC, GAA, GLA, JPH2, LAMP2, MTO1, MYBPC3, MYH7, MYL2, MYL3, PLN, PRKAG2, SLC25A4, TNNC1, TNNI3, TNNT2, TPM1 and TTR.

EXPANDED: 42 genes sequenced: ACADVL, ACTC1, ACTN2, AGL, ALPK3, ANKRD1, BAG3, CALR3, CAV3, CSRP3, DES, ELAC2, FHL1, FLNC, GAA, GATA4, GLA, JPH2, KLF10, LAMP2, MTO1, MYBPC3, MYH6, MYH7, MYL2, MYL3, MYLK2, MYOM1, MYOZ2, MYPN, PDLIM3, PLN, PRKAG2, RYR2, SLC25A4, TCAP, TNNC1, TNNI3, TNNT2, TPM1, TRIM63 and TTR.

*Familial Thoracic Aortic Aneurysm and Dissection panel

CORE: 18 genes sequenced: ACTA2, BGN, COL3A1, COL5A2, EFEMP2, FBN1, FBN2, FOXE3, LOX, MFAP5, MYH11, MYLK, PRKG1, SMAD2, SMAD3, TGFB2, TGFBR1 and TGFBR2.

EXPANDED: 25 genes sequenced: ACTA2, BGN, COL3A1, COL5A2, COL9A1, EFEMP2, FBN1, FBN2, FLNA, FOXE3, HCN4, LOX, MAT2A, MFAP5, MYH11, MYLK, NOTCH1, PRKG1, SLC2A10, SMAD2, SMAD3, TGFB2, TGFB3, TGFBR1 and TGFBR2.


Testing Methodology

Tests are performed using targeted hybridization capture coupled with next-generation sequencing (NGS) in our CAP/CLIA labs for comprehensive coverage of all coding exons of ordered genes.

Types of variation detected include single nucleotide variants (SNVs) and small insertions and deletions (indels).

For some cases with negative results or isolated heterozygous mutations in recessive genes, additional testing by alternate methodology may be performed to determine the presence of rare variant types not detected by this assay.


Results and Interpretation

DNA sequence data are analyzed by a clinically validated bioinformatics pipeline to identify and annotate genetic variants associated with the indication for testing.

Variants are interpreted by a board-certified clinical genomicist in the context of the patient’s disease and classified using the ACMG/AMP guidelines (Richards et al.), when present in core genes. Variants classified as being of potential clinical significance (pathogenic, likely pathogenic and VUS) are included in the clinical report.

Results are returned to the ordering physician in a concise report.

The turnaround time for testing and interpretation is approximately four weeks from the time a specimen arrives.


Specimen Requirements

Specimen types accepted include 2-5 mL peripheral blood in a lavender-top EDTA tube or 2-4 buccal swabs (please call the laboratory before sending buccal swabs). Specimen collection kits are available upon request.

***Previsouly extracted DNA can be accepted only with laboratory approval. The isolation of nucleic acids for clinical testing must have occurred in a CLIA-certified laboratory or a laboratory meeting equivalent requirements as determined by the CAP and/or the CMS.

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Clinical Utility

Genetic variation within a number of genes has now been described in association with cardiomyopathies and arrhythmias.

Determination of the underlying genetic cause of these heart disorders can aid in diagnosis and provide information of prognostic and therapeutic relevance.

Diagnosis – Observation of a known or expected pathogenic variant by genetic testing can solidify a clinical diagnosis allowing for appropriate patient management and surveillance and allows for screening of at-risk family members.

Prognosis – Genotype-phenotype relationships have been established in some forms of cardiac disease.

Knowledge of the causative genetic variant can provide information surrounding the genotype-specific natural history of the disease, response to pharmacotherapy, and symptom triggers.

Treatment – Therapeutic interventions exist for many forms of cardiac disease. Therapies may include drug or surgical interventions as appropriate for optimal patient management.

For example, use of beta blockers for management of patients with Long QT syndrome, or early, pre-emptive intervention with an implantable cardiac defibrillator may be considered in patients with dilated cardiomyopathy.