Massively Parallel Sequencing
Polymerase Chain Reaction/Sequencing
- Recommended test for a known familial sequence variant previously identified in a family member.
- A copy of the family member’s test result documenting the familial variant is required.
See Related Tests.
Inherited cardiomyopathy and arrhythmia disorders are genetically and phenotypically heterogeneous. Phenotypes include arrhythmogenic right ventricular cardiomyopathy (ARVC), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), left ventricular noncompaction (LVNC), long QT syndrome (LQTS), and short QT syndrome (SQTS). Genetic testing is used to confirm diagnosis.
Disease Overview
See Common Disorders table below.
Test Description
See Genes Tested table for genes included in the panel.
Clinical Sensitivity
Variable, dependent on phenotype/condition
- ARVC: 50 percent
- BrS: 15-30 percent
- CPVT: 60 percent
- DCM: 30-40 percent
- HCM (nonsyndromic familial): 50-60 percent
- LQTS: 60-75 percent
Limitations
- A negative result does not exclude a heritable form of cardiomyopathy or arrhythmia.
- Diagnostic errors can occur due to rare sequence variations.
- Interpretation of this test result may be impacted if the individual has had an allogeneic stem cell transplantation.
- The following will not be evaluated:
- Variants outside the coding regions and intron-exon boundaries of the targeted genes
- Variants in the mitochondrial genome
- Regulatory region variants and deep intronic variants
- Breakpoints of large deletions/duplications
- Deletions/duplications in BAG3, CRYAB, EMD, FHL1, GATAD1, TAZ, TRDN
- Noncoding transcripts
- The following exons are not sequenced due to technical limitations of the assay:
- TTN (NM_001267550) 172, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 215
- TTN (NM_133378) 153, 154, 155
- The following may not be detected:
- Deletions/duplications/insertions of any size by massively parallel sequencing
- Deletions/duplications less than 1kb in the targeted genes by array
- Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions
- Low-level somatic variants
- Single exon deletions/duplications in the following exons:
-
Gene Exon(s) ACTN2
(NM_001103) 17
CACNB2
(NM_001167945) 7
DMD
(NM_000109) 1
DSC2
(NM_024422) 1
DTNA
(NM_001390) 16, 21
KCNH2
(NM_000238) 13
KCNQ1
(NM_000218) 16
KCNQ1
(NM_181798) 1
MYBPC3
(NM_000256) 10, 24
MYH6
(NM_002471) 24, 28
MYH7
(NM_000257) 29
PKP2
(NM_004572) 6
PRKAG2
(NM_001304527) 1
PRKAG2
(NM_001304531) 2
PRKAG2
(NM_016203) 5
SGCB
(NM_000232) 1
SGCG
(NM_000231) 8
TGFB3
(NM_003239) 7
TRPM4
(NM_001321285) 4
TRPM4
(NM_017636) 7
TTN
(NM_001267550) 158, 173, 176, 185, 191, 194
TTN
(NM_133378) 114, 148, 155, 156, 167, 170
Analytical Sensitivity
For massively parallel sequencing:
Variant Class
Analytical Sensitivity (PPA) Estimatea (%)
Analytical Sensitivity (PPA) 95% Credibility Regiona (%)
SNVs
99.2
96.9-99.4
Deletions 1-10 bp
93.8
84.3-98.2
Deletions 11-44 bp
100
87.8-100
Insertions 1-10 bp
94.8
86.8-98.5
Insertions 11-23 bp
100
62.1-100
aGenes included on this test are a subset of a larger methods-based validation from which the PPA values are derived.
bp, base pairs; PPA, positive percent agreement; SNVs, single nucleotide variants
Common Disorders
Disorder | Clinical Characteristics | Prevalence | Inheritance | Comments |
---|---|---|---|---|
ARVC |
Progressive fibrofatty replacement of the myocardium predisposing to ventricular tachycardia and sudden death |
1/1,000 |
AD |
Commonly implicated genes include PKP2, DSP, DSG2 |
BrS |
Cardiac conduction abnormalities that can result in sudden death |
Unknown |
AD, 1% de novo |
Variants in SCN5A account for 15-30% of BrS |
CPVT |
Episodic syncope or ventricular arrhythmias occurring during exercise or acute emotion without presence of structural cardiac abnormalities |
1/10,000 |
AD or AR |
Variants in RYR2 account for 50-55% of all CPVT |
DCM |
Left ventricular enlargement and systolic dysfunction |
~1/500 |
Typically AD; AR/XL/Mitochondrial less common |
~20-35% of isolated DCM is familial Variants in TTN account for 10-20% of isolated DCM |
HCM |
Left ventricular hypertrophy with absence of other cardiovascular causes |
1/500 |
AD |
Variants in MYH7 and MYBPC3 account for majority of familial HCM. Variants in genes encoding for components of the sarcomere account for 55-70% of HCM with no multisystem involvement.
|
LVNC |
Hypertrophic and hypokinetic left ventricle with distinctive morphology |
Unknown |
Typically AD |
MYH7 and MYBPC3 commonly implicated genes |
LQTS |
Cardiac electrophysiologic disease with prolonged QT- and T-wave abnormalities on ECG associated with ventricular tachycardia (torsade de pointes) |
1/3,000 |
AD |
Incomplete penetrance |
SQTS |
Cardiac arrhythmia with short QT interval on ECG |
Unknown |
AD |
Associated genes: KCNH2, |
AD, autosomal dominant; AR, autosomal recessive; XL, X-linked |
Genes Tested
Gene |
MIM Number |
Disorder |
Inheritance |
---|---|---|---|
ABCC9 |
601439 |
Cantu syndrome Dilated cardiomyopathy, 1O Familial atrial fibrillation, 12 |
AD |
ACTC1 |
102540 |
Familial hypertrophic cardiomyopathy, 11 Atrial septal defect 5 Dilated cardiomyopathy, 1R Left ventricular noncompaction 4 |
AD |
ACTN2 |
102573 |
Dilated cardiomyopathy, 1AA, with or without LVNC Hypertrophic cardiomyopathy, 23, with or without LVNC |
AD |
ANK2 |
106410 |
Cardiac arrhythmia, ankyrin-B-related Long QT syndrome 4 |
AD |
ANKRD1 |
609599 |
Dilated cardiomyopathy |
AD |
BAG3 |
603883 |
Myofibrillar myopathy, 6 Dilated cardiomyopathy, 1HH |
AD |
CACNA1C |
114205 |
Timothy syndrome Brugada syndrome 3 |
AD |
CACNB2 |
600003 |
Brugada syndrome 4 |
AD |
CASQ2 |
114251 |
Catecholaminergic polymorphic ventricular tachycardia, 2 |
AR |
CAV3 |
601253 |
Familial hypertrophic cardiomyopathy, 1 Long QT syndrome 9 |
AD |
CRYAB |
123590 |
Myofibrillar myopathy, 2 Dilated cardiomyopathy, 1II |
AD |
Myofibrillar myopathy, fatal infantile hypertonic, alpha-B crystallin-related |
AR |
||
CSRP3 |
600824 |
Dilated cardiomyopathy, 1M Familial hypertrophic cardiomyopathy, 12 |
AD |
DES |
125660 |
Myofibrillar myopathy, 1 Dilated cardiomyopathy, 1I |
AD |
Myofibrillar myopathy, 1 |
AR |
||
DMD |
300377 |
Becker muscular dystrophy Dilated cardiomyopathy, 3B Duchenne muscular dystrophy |
XL |
DSC2 |
125645 |
Arrhythmogenic right ventricular dysplasia, 11 |
AD |
Arrhythmogenic right ventricular dysplasia 11 with mild palmoplantar keratoderma and woolly hair |
AR |
||
DSG2 |
125671 |
Arrhythmogenic right ventricular dysplasia, 10 Dilated cardiomyopathy, 1BB |
AD |
DSP |
125647 |
Arrhythmogenic right ventricular dysplasia, 8 Dilated cardiomyopathy with woolly hair, keratoderma, and tooth agenesis |
AD |
Dilated cardiomyopathy with woolly hair and keratoderma |
AR |
||
DTNA |
601239 |
Left ventricular noncompaction 1 |
AD |
EMD |
300384 |
Emery-Dreifuss muscular dystrophy 1 |
XL |
EYA4 |
603550 |
Dilated cardiomyopathy, 1J |
AD |
FHL1 |
300163 |
Uruguay faciocardiomusculoskeletal syndrome Scapuloperoneal myopathy Myopathy with postural muscle atrophy Emery-Dreifuss muscular dystrophy 6 Reducing body myopathy 1B, with late childhood or adult onset |
XL |
FKRP |
606596 |
Muscular dystrophy-dystroglycanopathy, type A, 5 Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 5 |
AR |
FKTN |
607440 |
Dilated cardiomyopathy, 1X Muscular dystrophy-dystroglycanopathy, type A, 4 |
AR |
GAA |
606800 |
Glycogen storage disease II |
AR |
GATAD1 |
614518 |
Dilated cardiomyopathy, 2B |
AR |
GLA |
300644 |
Fabry disease |
XL |
GPD1L |
611778 |
Brugada syndrome 2 |
AD |
JPH2 |
605267 |
Hypertrophic cardiomyopathy, 17 |
AD |
JUP |
173325 |
Arrhythmogenic right ventricular dysplasia, 12 |
AD |
Naxos disease |
AR |
||
KCNE1 |
176261 |
Long QT syndrome 5 |
AD |
Jervell and Lange-Nielsen syndrome 2 |
AR |
||
KCNE2 |
603796 |
Atrial fibrillation, familial, 4 Long QT syndrome 6 |
AD |
KCNE3 |
604433 |
Brugada syndrome 6 |
AD |
KCNH2 |
152427 |
Long QT syndrome 2 Short QT syndrome 1 |
AD |
KCNJ2 |
600681 |
Andersen syndrome Short QT syndrome 3 Atrial fibrillation, familial, 9 |
AD |
KCNQ1 |
607542 |
Long QT syndrome 1 Atrial fibrillation, familial, 3 Short QT syndrome 2 |
AD |
Jervell and Lange-Nielsen syndrome 1 |
AR |
||
LAMA4 |
600133 |
Dilated cardiomyopathy, 1JJ |
AD |
LAMP2 |
309060 |
Danon disease |
XL |
LDB3 |
605906 |
Dilated cardiomyopathy, 1C, with or without LVNC Hypertrophic cardiomyopathy, 24 Myofibrillar myopathy, 4 |
AD |
LMNA |
150330 |
Dilated cardiomyopathy, 1A Emery-Dreifuss muscular dystrophy 2 Heart-hand syndrome, Slovenian type Muscular dystrophy, congenital Malouf syndrome |
AD |
Emery-Dreifuss muscular dystrophy 3 |
AR |
||
MYBPC3 |
600958 |
Hypertrophic cardiomyopathy, 4 Dilated cardiomyopathy, 1MM Left ventricular noncompaction 10 |
AD |
MYH6 |
160710 |
Dilated cardiomyopathy, 1EE Hypertrophic cardiomyopathy, 14 |
AD |
MYH7 |
160760 |
Laing distal myopathy Hypertrophic cardiomyopathy 1 Dilated cardiomyopathy, 1S Left ventricular noncompaction 5 |
AD |
Myopathy, myosin storage |
AR |
||
MYL2 |
160781 |
Hypertrophic cardiomyopathy, 10 |
AD |
MYL3 |
160790 |
Hypertrophic cardiomyopathy, 8 |
AD/AR |
MYLK2 |
606566 |
Hypertrophy cardiomyopathy, 1 |
AD |
MYOT |
604103 |
Myofibrillar myopathy, 3 |
AD |
MYOZ2 |
605602 |
Hypertrophic cardiomyopathy, 16 |
AD |
MYPN |
608517 |
Dilated cardiomyopathy, 1KK Familial restrictive cardiomyopathy 4 Hypertrophic cardiomyopathy 22 |
AD |
Nemaline myopathy 11 |
AR |
||
NEXN |
613121 |
Dilated cardiomyopathy, 1CC Hypertrophic cardiomyopathy, 20 |
AD |
PKP2 |
602861 |
Arrhythmogenic right ventricular dysplasia, 9 |
AD |
PLN |
172405 |
Dilated cardiomyopathy, 1P Hypertrophic cardiomyopathy, 18 |
AD |
PRKAG2 |
602743 |
Hypertrophic cardiomyopathy, 6 Glycogen storage disease of the heart, lethal congenital Wolff-Parkinson-White syndrome |
AD |
RBM20 |
613171 |
Dilated cardiomyopathy, 1DD |
AD |
RYR2 |
180902 |
Arrhythmogenic right ventricular dysplasia, 2 Catecholaminergic polymorphic ventricular tachycardia, 1 |
AD |
SCN1B |
600235 |
Brugada syndrome 5 Cardiac conduction defect, nonspecific Atrial fibrillation, familial, 13 |
AD |
SCN2B |
601327 |
Atrial fibrillation, familial, 14 |
AD |
SCN3B |
608214 |
Brugada syndrome 7 Atrial fibrillation, familial, 16 |
AD |
SCN4B |
608256 |
Long QT syndrome 10 Atrial fibrillation, familial, 17 |
AD |
SCN5A |
600163 |
Heart block, progressive, type IA Heart block, nonprogressive Brugada syndrome 1 Cardiomyopathy, dilated, 1E Ventricular fibrillation, paroxysmal familial, 1 Long QT syndrome 3 Atrial fibrillation, familial, 10 |
AD |
Sick sinus syndrome 1 |
AR |
||
SGCA |
600119 |
Muscular dystrophy, limb-girdle, type 2D |
AR |
SGCB |
600900 |
Muscular dystrophy, limb-girdle, type 2E |
AR |
SGCD |
601411 |
Muscular dystrophy, limb-girdle, type 2F |
AR |
Dilated cardiomyopathy, 1L |
AD |
||
SGCG |
608896 |
Muscular dystrophy, limb-girdle, type 2C |
AR |
SLC25A4 |
103220 |
Mitochondrial DNA depletion syndrome 12A |
AD |
Mitochondrial DNA depletion syndrome 12B |
AR |
||
SNTA1 |
601017 |
Long QT syndrome 12 |
AD |
TAZ |
300394 |
Barth syndrome |
XL |
TCAP |
604488 |
Hypertrophic cardiomyopathy, 25 |
AD |
Muscular dystrophy, limb-girdle, type 2G |
AR |
||
TGFB3 |
190230 |
Arrhythmogenic right ventricular dysplasia, 1 |
AD |
TMEM43 |
612048 |
Arrhythmogenic right ventricular dysplasia, 5 Emery-Dreifuss muscular dystrophy 7 |
AD |
TNNC1 |
191040 |
Dilated cardiomyopathy, 1Z Hypertrophic cardiomyopathy, 13 |
AD |
TNNI3 |
191044 |
Dilated cardiomyopathy, 1FF Cardiomyopathy, familial restrictive, 1 Hypertrophic cardiomyopathy, 7 |
AD |
Dilated cardiomyopathy, 2A |
AR |
||
TNNT2 |
191045 |
Hypertrophic cardiomyopathy, 2 Dilated cardiomyopathy, 1D Left ventricular noncompaction 6 Cardiomyopathy, familial restrictive, 3 |
AD |
TPM1 |
191010 |
Hypertrophic cardiomyopathy, 3 Dilated cardiomyopathy, 1Y Left ventricular noncompaction 9 |
AD |
TRDN |
603283 |
Catecholaminergic polymorphic ventricular tachycardia, 5, with or without muscle weakness |
AR |
TRPM4 |
606936 |
Progressive familial heart block, type IB |
AD |
TTN |
188840 |
Dilated cardiomyopathy, 1G Hypertrophic cardiomyopathy, 9 |
AD |
Salih myopathy |
AR |
||
TTR |
176300 |
Amyloidosis, hereditary, transthyretin-related |
AD |
VCL |
193065 |
Hypertrophic cardiomyopathy, 15 Dilated cardiomyopathy, 1W |
AD |
AD, autosomal dominant; AR, autosomal recessive, XL, X-linked |
References
-
GeneReviews - Arrhythmogenic Right Ventricular Cardiomyopathy
McNally E, MacLeod H, Dellefave-Castillo L. Arrhythmogenic Right Ventricular Cardiomyopathy. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, University of Washington; 1993-2020. [Last Update: May 2017; Accessed: Feb 2020]
-
GeneReviews - Brugada Syndrome
Brugada R, Campuzano O, Sarquella-Brugada G, et al. Brugada Syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, University of Washington; 1993-2020. [Last Update: Nov 2016; Accessed: Feb 2020]
-
GeneReviews - Catecholaminergic Polymorphic Ventricular Tachycardia
Napolitano C, Priori SG, Bloise R. Catecholaminergic Polymorphic Ventricular Tachycardia. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, University of Washington; 1993-2020. [Last Update: Oct 2016; Accessed: Feb 2020]
-
GeneReviews - Dilated Cardiomyopathy Overview
Hershberger RE, Morales A. Dilated cardiomyopathy overview. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews, University of Washington; 1993-2021. [Last Update: Aug 2018; Accessed: Mar 2020]
-
GeneReviews - Hypertrophic Cardiomyopathy Overview
Cirino AL, Ho C. Hypertrophic cardiomyopathy overview. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews, University of Washington; 1993-2021. [Last Update: Jun 2019; Accessed: Feb 2020]
-
GeneReviews - Long QT Syndrome
Alders M, Bikker H, Christiaans I. Long QT syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, editors. GeneReviews, University of Washington; 1993-2021. [Last Update: Feb 2018; Accessed: Feb 2021]
Use to confirm hereditary form of cardiomyopathy or arrhythmia.