Cardiomyopathy Panel

Last modified: May 04, 2018

Summary

  • Is a 155 gene panel that includes assessment of non-coding variants
  • Is ideal for patients with a clinical suspicion of atypical or complex cardiomyopathy phenotypes.

Analysis methods

  • PLUS
  • SEQ
  • DEL/DUP

Availability

3-4 weeks

Number of genes

155

Test code

CA1201

CPT codes

SEQ 81439
DEL/DUP 81479

Summary

The Blueprint Genetics Cardiomyopathy Panel (test code CA1201):

  • Is a 155 gene panel that includes assessment of selected non-coding disease-causing variants
  • Is available as PLUS analysis (sequencing analysis and deletion/duplication analysis), sequencing analysis only or deletion/duplication analysis only

ICD codes

Commonly used ICD-10 code(s) when ordering the Cardiomyopathy Panel

ICD-10 Disease
I42.5 RCM
I42.9 Cardiomyopathy NAS
Q87.1 Noonan syndrome
I42.2 Hypertrophic cardiomyopathy (HCM)
I42.0 Dilated cardiomyopathy (DCM)
I42.8 Arrhythmogenic right ventricular cardiomyopathy (ARVC)
I42.8 Left ventricular non-compaction cardiomyopathy (LVNC)

Sample Requirements

  • EDTA blood, min. 1 ml
  • Purified DNA, min. 3μg
  • Saliva (Oragene DNA OG-500 kit)

Label the sample tube with your patient’s name, date of birth and the date of sample collection.

Note that we do not accept DNA samples isolated from formalin-fixed paraffin-embedded (FFPE) tissue.

Subpanel description

This comprehensive panel includes genes from the following panels: Hypertrophic Cardiomyopathy (HCM) Panel, Dilated Cardiomyopathy (DCM) Panel, Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) Panel and Left Ventricular Non-Compaction Cardiomyopathy (LVNC) Panel.

Cardiomyopathies are a group of severe cardiac diseases with a strong genetic background. Cardiomyopathies are all associated with significantly increased risk of heart failure and sudden cardiac death. According to the European Society of Cardiology (ESC) classification (Charron et al. 2010), cardiomyopathies can be divided into five subgroups according to structural and functional changes of the myocardium: 1) hypertrophic cardiomyopathy (HCM), 2) dilated cardiomyopathy (DCM), 3) arrhythmogenic right ventricular cardiomyopathy (ARVC), 4) restrictive cardiomyopathy (RCM) and 5) non-classified cardiomyopathies such as isolated left ventricular non-compaction cardiomyopathy (LVNC). Thousands of causative cardiomyopathy mutations have been characterized from more than 100 genes to date. These genes encode proteins making up the structure of the sarcomere, cytoskeleton, desmosome, ion channels or nuclear lamina, and proteins participating in Ca2+ handling during the contraction phase of action potential or affecting cardiac energy metabolism. In addition, there are several disorders that may result in congenital or early childhood-onset cardiomyopathty.

Genes in the Cardiomyopathy Panel and their clinical significance

Gene Associated phenotypes Inheritance ClinVar HGMD
AARS2 Leukoencephalopathy, progressive, with ovarian failure AR 14 26
ABCC6* Pseudoxanthoma elasticum AR 374 297
ABCC9 Atrial fibrillation, Cantu syndrome, Dilated cardiomyopathy (DCM) AD 24 36
ACAD9 Acyl-CoA dehydrogenase family, deficiency AR 23 42
ACADVL Acyl-CoA dehydrogenase, very long chain, deficiency AR 94 260
ACTA1 Myopathy AD/AR 50 206
ACTC1 Left ventricular noncompaction, Hypertrophic cardiomyopathy (HCM), Cardiomyopathy, restrictive, Atrial septal defect, Dilated cardiomyopathy (DCM) AD 23 54
ACTN2 Hypertrophic cardiomyopathy (HCM), Dilated cardiomyopathy (DCM) AD 8 31
AGK* Sengers syndrome, Cataract 38 AR 15 21
AGL Glycogen storage disease AR 82 242
ALMS1* Alström syndrome AR 50 291
ALPK3 Pediatric cardiomyopathy AR 6 4
ANO5 Gnathodiaphyseal dysplasia, LGMD2L and distal MMD3 muscular dystrophies AD/AR 49 115
APOA1 Amyloidosis, systemic nonneuronopathic, Hypoalphalipoproteinemia AD/AR 26 69
BAG3 Dilated cardiomyopathy (DCM), Myopathy, myofibrillar AD 30 50
BRAF* LEOPARD syndrome, Noonan syndrome, Cardiofaciocutaneous syndrome AD 131 62
CALR3 Cardiomyopathy, familial hypertrophic, 19 AD 3
CAPN3 Muscular dystrophy, limb-girdle, Eosinophilic myositis AR 108 427
CASQ2 Ventricular tachycardia, catecholaminergic, polymorphic AR 21 32
CBL Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia AD 23 36
CDH2 Arrhythmogenic right ventricular cardiomyopathy (ARVC) AD 4
COX15 Leigh syndrome, Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency AR 7 5
CPT2 Carnitine palmitoyltransferase II deficiency AR 47 104
CRYAB Cataract, myofibrillar myopathy and cardiomyopathy, Congenital cataract and cardiomyopathy, Dilated cardiomyopathy (DCM), Myopathy, myofibrillar AD 16 27
CSRP3 Hypertrophic cardiomyopathy (HCM), Dilated cardiomyopathy (DCM) AD 5 23
CTNNA3 Arrhythmogenic right ventricular dysplasia AD 6 39
DBH Dopamine beta-hydroxylase deficiency AR 10 13
DES Dilated cardiomyopathy (DCM), Myopathy, myofibrillar, Scapuloperoneal syndrome, neurogenic, Kaeser type AD/AR 57 109
DMD Becker muscular dystrophy, Duchenne muscular dystrophy, Dilated cardiomyopathy (DCM) XL 610 3620
DNAJC19 3-methylglutaconic aciduria AR 3 3
DOLK Congenital disorder of glycosylation AR 7 10
DSC2 Arrhythmogenic right ventricular dysplasia with palmoplantar keratoderma and woolly hair, Arrhythmogenic right ventricular dysplasia AD/AR 23 80
DSG2 Arrhythmogenic right ventricular dysplasia, Dilated cardiomyopathy (DCM) AD 37 117
DSP Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis, Arrhythmogenic right ventricular dysplasia, familial, Cardiomyopathy, dilated, with wooly hair and keratoderma, Keratosis palmoplantaris striata II, Epidermolysis bullosa, lethal acantholytic AD/AR 128 262
DTNA Left ventricular noncompaction 1 AD 3 5
DYSF Miyoshi muscular dystrophy, Muscular dystrophy, limb-girdle, Myopathy, distal, with anterior tibial onset AR 155 517
EEF1A2 Epileptic encephalopathy, early infantile, Mental retardation AD 10 10
ELAC2 Combined oxidative phosphorylation deficiency 17 AR 6 14
EMD Emery-Dreifuss muscular dystrophy XL 40 112
EPG5 Vici syndrome AR 20 48
ETFA Glutaric aciduria, Multiple acyl-CoA dehydrogenase deficiency AR 8 27
ETFB Glutaric aciduria, Multiple acyl-CoA dehydrogenase deficiency AR 6 14
ETFDH Glutaric aciduria, Multiple acyl-CoA dehydrogenase deficiency AR 37 169
FBXO32 Dilated cardiomyopathy (DCM) AD/AR 2
FHL1* Myopathy with postural muscle atrophy, Emery-Dreifuss muscular dystrophy, Reducing bod myopathy XL 21 59
FKRP Muscular dystrophy-dystroglycanopathy AR 36 114
FKTN Muscular dystrophy-dystroglycanopathy, Dilated cardiomyopathy (DCM), Muscular dystrophy-dystroglycanopathy (limb-girdle) AD/AR 34 53
FLNC* Myopathy AD 16 87
FOXD4* Dilated cardiomyopathy (DCM) AD 1
FOXRED1 Leigh syndrome, Mitochondrial complex I deficiency AR 12 7
FXN* Friedreich ataxia AR 11 62
GAA Glycogen storage disease AR 136 528
GATA6 Heart defects, congenital, and other congenital anomalies AD 16 76
GATAD1 Dilated cardiomyopathy (DCM) AR 21 1
GBE1 Glycogen storage disease AR 30 71
GFM1 Combined oxidative phosphorylation deficiency AR 17 18
GLA Fabry disease XL 188 910
GLB1 GM1-gangliosidosis, Mucopolysaccharidosis (Morquio syndrome) AR 60 212
GMPPB Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), Limb-girdle muscular dystrophy-dystroglycanopathy AR 13 29
GTPBP3 Combined oxidative phosphorylation deficiency 23 AR 8 15
GUSB* Mucopolysaccharidosis AR 24 61
HADHA Trifunctional protein deficiency, Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency AR 42 68
HAND1 Congenital heart defects, Dilated cardiomyopathy AD 7
HCN4 Sick sinus syndrome, Brugada syndrome AD 11 27
HFE Hemochromatosis AR/Digenic 9 53
HRAS Costello syndrome, Congenital myopathy with excess of muscle spindles AD 39 27
ISPD Muscular dystrophy-dystroglycanopathy AR 23 44
JPH2 Hypertrophic cardiomyopathy (HCM) AD 4 10
JUP Arrhythmogenic right ventricular dysplasia, Naxos disease AD/AR 8 38
KRAS* Noonan syndrome, Cardiofaciocutaneous syndrome AD 59 31
LAMA2 Muscular dystrophy, congenital merosin-deficient AR 90 256
LAMP2 Danon disease XL 54 94
LARGE Muscular dystrophy-dystroglycanopathy AR 15 25
LDB3 Dilated cardiomyopathy (DCM), Myopathy, myofibrillar AD 9 12
LMNA Heart-hand syndrome, Slovenian, Limb-girdle muscular dystrophy, Muscular dystrophy, congenital, LMNA-related, Lipodystrophy (Dunnigan), Emery-Dreiffus muscular dystrophy, Malouf syndrome, Dilated cardiomyopathy (DCM), Mandibuloacral dysplasia type A, Progeria Hutchinson-Gilford type AD/AR 211 513
LRRC10 Dilated cardiomyopathy (DCM) AD/AR 4
LZTR1 Schwannomatosis, Noonan syndrome AD 18 62
MAP2K1 Cardiofaciocutaneous syndrome AD 43 21
MAP2K2 Cardiofaciocutaneous syndrome AD 21 34
MLYCD Malonyl-CoA decarboxylase deficiency AR 13 38
MTO1 Combined oxidative phosphorylation deficiency AR 10 13
MYBPC3 Left ventricular noncompaction, Hypertrophic cardiomyopathy (HCM), Dilated cardiomyopathy (DCM) AD 423 987
MYBPHL Dilated cardiomyopathy (DCM) AD
MYH6 Hypertrophic cardiomyopathy (HCM), Dilated cardiomyopathy (DCM), Atrial septal defect 3 AD 12 75
MYH7 Hypertrophic cardiomyopathy (HCM), Myopathy, myosin storage, Myopathy, distal, Dilated cardiomyopathy (DCM) AD 289 923
MYL2 Hypertrophic cardiomyopathy (HCM), Infantile type I muscle fibre disease and cardiomyopathy AD 20 60
MYL3 Hypertrophic cardiomyopathy (HCM) AD/AR 14 37
MYL4 Atrial fibrillation, familial, 18 AD 2 2
MYOT Myopathy, myofibrillar AD 8 16
MYPN Hypertrophic cardiomyopathy (HCM), Cardiomyopathy, restrictive, Dilated cardiomyopathy (DCM), Nemaline myopathy 11, autosomal recessive AD 6 36
NDUFAF2 Mitochondrial complex I deficiency, Leigh syndrome AR 6 8
NEXN Hypertrophic cardiomyopathy (HCM), Dilated cardiomyopathy (DCM) AD 6 30
NF1* Watson syndrome, Neurofibromatosis, Neurofibromatosis-Noonan syndrome AD 592 2681
NRAS Noonan syndrome AD 31 14
PCCA Propionic acidemia AR 43 120
PCCB Propionic acidemia AR 40 111
PKP2* Arrhythmogenic right ventricular dysplasia AD 116 269
PLEC Muscular dystrophy, limb-girdle, Epidermolysis bullosa AR 26 91
PLEKHM2 Dilated cardiomyopathy (DCM), left ventricular noncompaction AR 1 1
PLN Hypertrophic cardiomyopathy (HCM), Dilated cardiomyopathy (DCM) AD/AR 8 28
PNPLA2 Neutral lipid storage disease with myopathy AR 11 36
PPA2 Sudden cardiac failure, infantile AR 8 8
PPP1CB# Noonan syndrome-like disorder with loose anagen hair 2 AD 6 7
PRDM16 Left ventricular noncompaction, Dilated cardiomyopathy (DCM) AD 16 11
PRKAG2# Hypertrophic cardiomyopathy (HCM), Wolff-Parkinson-White syndrome, Glycogen storage disease of heart, lethal congenital AD 19 53
PTPN11 LEOPARD syndrome, Noonan syndrome, Metachondromatosis AD 124 135
RAF1 LEOPARD syndrome, Noonan syndrome, Dilated cardiomyopathy (DCM) AD 44 43
RASA2# Noonan syndrome AD 1 3
RBCK1 Polyglucosan body myopathy AR 8 14
RBM20 Dilated cardiomyopathy (DCM) AD 16 31
RIT1 Noonan syndrome AD 21 24
RMND1* Combined oxidative phosphorylation deficiency AR 15 15
RRAS Noonan-syndrome like phenotype AD/AR 2
RYR2 Ventricular tachycardia, catecholaminergic polymorphic, Arrhythmogenic right ventricular dysplasia AD 110 329
SCN5A Heart block, nonprogressive, Heart block, progressive, Long QT syndrome, Ventricular fibrillation, Atrial fibrillation, Sick sinus syndrome, Brugada syndrome, Dilated cardiomyopathy (DCM) AD/AR/Digenic 212 819
SCNN1B Liddle syndrome, Pseudohypoaldosteronism, Bronchiectasis with or without elevated sweat chloride AD/AR 14 45
SCNN1G Liddle syndrome, Pseudohypoaldosteronism, Bronchiectasis with or without elevated sweat chloride AD/AR 5 18
SCO2 Leigh syndrome, Hypertrophic cardiomyopathy (HCM), Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency, Myopia AR 42 33
SDHA* Leigh syndrome/Mitochondrial respiratory chain complex II deficiency, Gastrointestinal stromal tumor, Paragangliomas, Dilated cardiomyopathy (DCM), Cardiomyopathy, dilated, 1GG AD/AR 29 51
SELENON Muscular dystrophy, rigid spine, Myopathy, congenital, with fiber- disproportion AR 27 59
SGCA Muscular dystrophy, limb-girdle AR 40 99
SGCB Muscular dystrophy, limb-girdle AR 22 59
SGCD Muscular dystrophy, limb-girdle, Dilated cardiomyopathy (DCM) AR 14 20
SGCG Muscular dystrophy, limb-girdle AR 19 57
SHOC2 Noonan-like syndrome with loose anagen hair AD 2 4
SLC22A5 Carnitine deficiency, systemic primary AR 76 117
SLC25A4 Progressive external ophthalmoplegia with mitochondrial DNA deletions, Mitochondrial DNA depletion syndrome AD/AR 12 13
SLC25A20 Carnitine-acylcarnitine translocase deficiency AR 11 41
SMCHD1 Facioscapulohumeral muscular dystrophy, Facioscapulohumeral muscular dystrophy, type 2 Digenic (involving a SMCHD1 mutation and permissive D4Z4 haplotype) 37 71
SOS1 Noonan syndrome AD 45 66
SOS2 Noonan syndrome 9 AD 3 6
SPEG Centronuclear myopathy 5 AR 5 6
SPRED1 Legius syndrome AD 18 70
TAB2 Congenital heart defects, multiple types, 2 AD 9 25
TAZ 3-Methylglutaconic aciduria, (Barth syndrome) XL 39 151
TBX5 Holt-Oram syndrome AD 42 123
TBX20* Atrial septal defect 4 AD 3 23
TCAP Muscular dystrophy, limb-girdle, Hypertrophic cardiomyopathy (HCM), Dilated cardiomyopathy (DCM) AD/AR 10 26
TGFB3 Loeys-Dietz syndrome (Reinhoff syndrome), Arrhythmogenic right ventricular dysplasia AD 13 19
TMEM43 Arrhythmogenic right ventricular dysplasia, Emery-Dreifuss muscular dystrophy AD 5 20
TMEM70 Mitochondrial complex V (ATP synthase) deficiency AR 10 18
TNNC1 Hypertrophic cardiomyopathy (HCM), Dilated cardiomyopathy (DCM) AD 9 20
TNNI3 Hypertrophic cardiomyopathy (HCM), Cardiomyopathy, restrictive, Dilated cardiomyopathy (DCM) AD/AR 55 121
TNNI3K Cardiac conduction disease with or without dilated cardiomyopathy AD 1 2
TNNT2 Left ventricular noncompaction, Hypertrophic cardiomyopathy (HCM), Cardiomyopathy, restrictive, Dilated cardiomyopathy (DCM) AD 61 132
TOR1AIP1 Muscular dystrophy with progressive weakness, distal contractures and rigid spine AD/AR 1 5
TPM1 Hypertrophic cardiomyopathy (HCM), Dilated cardiomyopathy (DCM) AD 39 90
TRIM32 Bardet-Biedl syndrome, Muscular dystrophy, limb-girdle AR 11 16
TSFM Combined oxidative phosphorylation deficiency AR 7 6
TTN* Dilated cardiomyopathy (DCM), Tibial muscular dystrophy, Limb-girdle muscular dystrophy, Hereditary myopathy with early respiratory failure, Myopathy, early-onset, with fatal cardiomyopathy (Salih myopathy), Muscular dystrophy, limb-girdle, type 2J AD 576 271
TTR Dystransthyretinemic hyperthyroxinemia, Amyloidosis, hereditary, transthyretin-related AD 50 141
VCL Hypertrophic cardiomyopathy (HCM), Dilated cardiomyopathy (DCM) AD 12 24
VCP Amyotrophic lateral sclerosis, Inclusion body myopathy with early-onset Paget disease, Charcot-Marie-Tooth disease AD 16 54
VPS13A Choreoacanthocytosis AR 16 113
XK McLeod syndrome XL 9 37

* Some, or all, of the gene is duplicated in the genome. Read more.

# The gene has suboptimal coverage (means <90% of the gene’s target nucleotides are covered at >20x with mapping quality score (MQ>20) reads).

The sensitivity to detect variants may be limited in genes marked with an asterisk (*) or number sign (#)

Gene refers to the HGNC approved gene symbol; Inheritance refers to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR), X-linked (XL), X-linked dominant (XLD) and X-linked recessive (XLR); ClinVar refers to the number of variants in the gene classified as pathogenic or likely pathogenic in this database (ClinVar); HGMD refers to the number of variants with possible disease association in the gene listed in Human Gene Mutation Database (HGMD). The list of associated, gene specific phenotypes are generated from CGD or Orphanet databases.

Non-coding variants covered by the panel

Gene Genomic location HG19 HGVS RefSeq RS-number
ABCC6 Chr16:16281097 c.1780-29T>A NM_001171.5 rs72664206
ACADVL Chr17:7126948 c.1252-15A>G NM_001270447.1 rs765390290
ACADVL Chr17:7125485 c.822-11T>G NM_001270447.1
ACADVL Chr17:7125469 c.822-27C>T NM_001270447.1 rs374911841
ACTC1 Chr15:35080829 c.*1784T>C NM_005159.4
AGL Chr1:100381954 c.4260-12A>G NM_000028.2 rs369973784
APOA1 Chr11:116708299 c.-21+22G>A NM_000039.1
APOA1 Chr11:116708365 c.-65A>C NM_000039.1
CAPN3 Chr15:42695919 c.1746-20C>T NM_000070.2
CAPN3 Chr15:42702770 c.2185-16A>G NM_000070.2
CAPN3 Chr15:42678352 c.380-13T>A NM_000070.2
DMD ChrX:32644479 c.1332-11909C>G NM_004006.2
DMD ChrX:32841967 c.265-463A>G NM_004006.2
DMD ChrX:33192452 c.31+36947G>A NM_004006.2
DMD ChrX:32479520 c.3432+2036A>G NM_004006.2
DMD ChrX:32479316 c.3432+2240A>G NM_004006.2
DMD ChrX:32460274 c.3787-843C>A NM_004006.2
DMD ChrX:32398808 c.4675-11A>G NM_004006.2
DMD ChrX:32827744 c.531-16T>A/G NM_004006.2
DMD ChrX:32366860 c.5326-215T>G NM_004006.2
DMD ChrX:32360414 c.5740-15G>T NM_004006.2
DMD ChrX:32274692 c.6290+30954C>T NM_004006.2
DMD ChrX:31983146 c.6614+3310G>T NM_004006.2 rs797045526
DMD ChrX:31897527 c.6913-4037T>G NM_004006.2
DMD ChrX:31627738 c.8217+18052A>G NM_004006.2
DMD ChrX:31613687 c.8217+32103G>T NM_004006.2
DMD ChrX:32716130 c.832-15A>G NM_004006.2 rs72470513
DMD ChrX:31382270 c.9085-15519G>T NM_004006.2
DMD ChrX:31332523 c.9224+9192C>A NM_004006.2
DMD ChrX:31279293 c.9225-160A>G NM_004006.2
DMD ChrX:31279418 c.9225-285A>G NM_004006.2
DMD ChrX:31279780 c.9225-647A>G NM_004006.2 rs398124091
DMD ChrX:31279781 c.9225-648A>G NM_004006.2 rs398124084
DMD ChrX:33032666 c.93+5590T>A NM_004006.2
DMD ChrX:31229031 c.9362-1215A>G NM_004006.2
DMD ChrX:31226400 c.9563+1215A>G NM_004006.2
DMD ChrX:31224814 c.9564-30A>T NM_004006.2
DMD ChrX:31225211 c.9564-427T>G NM_004006.2
DMD ChrX:32669100 c.961-5831C>T NM_004006.2 rs398124099
DMD ChrX:32669194 c.961-5925A>C NM_004006.2
DMD ChrX:31219364 c.9807+2714C>T NM_004006.2
DSC2 Chr18:28683379 c.-1445G>C NM_024422.4 rs75494355
DYSF Chr2:71817308 c.3443-33A>G NM_003494.3 rs786205083
DYSF Chr2:71840553 c.4410+13T>G NM_003494.3
DYSF Chr2:71889030 c.4886+1249G>T NM_003494.3
ETFDH Chr4:159593534 c.-75A>G NM_004453.2
FKTN Chr9:108368857 c.648-1243G>T NM_006731.2
GAA Chr17:78078369 c.-17C>T NM_000152.3
GAA Chr17:78078341 c.-32-13T>A NM_000152.3
GAA Chr17:78078341 c.-32-13T>G NM_000152.3 rs386834236
GAA Chr17:78078352 c.-32-2A>G NM_000152.3
GAA Chr17:78078351 c.-32-3C>A NM_000152.3
GAA Chr17:78078351 c.-32-3C>A/G NM_000152.3
GAA Chr17:78082266 c.1076-22T>G NM_000152.3 rs762260678
GAA Chr17:78092432 c.2647-20T>G NM_000152.3
GATA6 Chr18:19749272 c.-409C>G NM_005257.4
GATA6 Chr18:19749151 c.-530A>T NM_005257.4
GBE1 Chr3:81542963 c.2053-3358_2053-3350delGTGTGGTGGinsTGTTTTTTACATGACAGGT NM_000158.3
GLA ChrX:100656225 c.547+395G>C NM_000169.2
GLA ChrX:100653945 c.640-11T>A NM_000169.2
GLA ChrX:100654735 c.640-801G>A NM_000169.2 rs199473684
GLA ChrX:100654793 c.640-859C>T NM_000169.2 rs869312374
HFE Chr6:26087649 c.-20G>A NM_000410.3 rs138378000
LAMA2 Chr6:129636608 c.3556-13T>A NM_000426.3 rs775278003
LAMA2 Chr6:129714172 c.5235-18G>A NM_000426.3 rs188365084
LAMP2 ChrX:119604078 c.-1054A>C NM_001122606.1
LMNA Chr1:156107037 c.1608+14G>A NM_170707.3
LMNA Chr1:156107433 c.1609-12T>G NM_170707.3 rs267607582
LMNA Chr1:156100609 c.513+45T>G NM_170707.3
LMNA Chr1:156105681 c.937-11C>G NM_170707.3 rs267607645
LZTR1 Chr22:21340117 c.264-13G>A NM_006767.3 rs587777176
MLYCD Chr16:83948547 c.949-14A>G NM_012213.2 rs761146008
MYBPC3 Chr11:47353394 c.*26+2T>C NM_000256.3
MYBPC3 Chr11:47364832 c.1224-19G>A NM_000256.3 rs587776699
MYBPC3 Chr11:47364814 c.1224-1G>T NM_000256.3 rs767405420
MYBPC3 Chr11:47364815 c.1224-2A>G NM_000256.3 rs397515891
MYBPC3 Chr11:47364709 c.1227-13G>A NM_000256.3 rs397515893
MYBPC3 Chr11:47360310 c.2149-80G>A NM_000256.3
MYBPC3 Chr11:47359371 c.2309-26A>G NM_000256.3
MYBPC3 Chr11:47368581 c.906-1G>C NM_000256.3 rs587776700
MYBPC3 Chr11:47368616 c.906-36G>A NM_000256.3 rs864622197
NEXN Chr1:78381662 c.-52-78C>A NM_144573.3
NF1 Chr17:29422056 c.-272G>A NM_001042492.2
NF1 Chr17:29422055 c.-273A>C NM_001042492.2
NF1 Chr17:29530107 c.1260+1604A>G NM_001042492.2
NF1 Chr17:29533239 c.1261-19G>A NM_001042492.2
NF1 Chr17:29534143 c.1392+754T>G NM_001042492.2
NF1 Chr17:29488136 c.288+2025T>G NM_001042492.2
NF1 Chr17:29577934 c.4110+1802delA NM_001042492.2 rs863224944
NF1 Chr17:29577082 c.4110+945A>G NM_001042492.2
NF1 Chr17:29580296 c.4173+278A>G NM_001042492.2
NF1 Chr17:29654479 c.5269-38A>G NM_001042492.2
NF1 Chr17:29656858 c.5610-456G>T NM_001042492.2
NF1 Chr17:29657848 c.5812+332A>G NM_001042492.2 rs863224491
NF1 Chr17:29508428 c.587-12T>A NM_001042492.2
NF1 Chr17:29508426 c.587-14T>A NM_001042492.2
NF1 Chr17:29664375 c.6428-11T>G NM_001042492.2
NF1 Chr17:29664618 c.6642+18A>G NM_001042492.2
NF1 Chr17:29676126 c.7190-12T>A NM_001042492.2
NF1 Chr17:29685481 c.7971-17C>G NM_001042492.2
NF1 Chr17:29685177 c.7971-321C>G NM_001042492.2
NF1 Chr17:29685665 c.8113+25A>T NM_001042492.2
NF1 Chr17:29510334 c.888+651T>A NM_001042492.2
NF1 Chr17:29510427 c.888+744A>G NM_001042492.2
NF1 Chr17:29510472 c.888+789A>G NM_001042492.2
PCCA Chr13:100958030 c.1285-1416A>G NM_000282.3
PCCB Chr3:136003251 c.714+462A>G NM_001178014.1
PLN Chr6:118869417 c.-236C>G NM_002667.4 rs188578681
PLN Chr6:118869382 c.-271A>G NM_002667.4
PTPN11 Chr12:112915602 c.934-59T>A NM_002834.3
SELENON Chr1:26143316 c.*1107T>C NM_020451.2
SGCG Chr13:23755215 c.-1+1G>T NM_000231.2
SLC22A5 Chr5:131714054 c.394-16T>A NM_003060.3 rs775097754
SLC22A5 Chr5:131722665 c.825-52G>A NM_003060.3
SMCHD1 Chr18:2701019 c.1647+103A>G NM_015295.2
TBX20 Chr7:35293780 c.-549G>A NM_001077653.2 rs571512677
TBX5 Chr12:114704515 c.*88822C>A NM_000192.3 rs141875471
TGFB3 Chr14:76425035 c.*495C>T NM_003239.2 rs387906514
TGFB3 Chr14:76447266 c.-30G>A NM_003239.2 rs770828281
VCP Chr9:35072710 c.-360G>C NM_007126.3

Added and removed genes from the panel

Genes added Genes removed
ABCC6
ALMS1
CALR3
CDH2
DOLK
DTNA
EEF1A2
ELAC2
EPG5
FOXD4
GATA6
GTPBP3
HADHA
HAND1
LRRC10
MLYCD
MYBPHL
MYL4
NDUFAF2
PCCA
PCCB
PPA2
PPP1CB
RBCK1
RMND1
SOS2
SPEG
TAB2
TBX20
TBX5
TNNI3K
TOR1AIP1
VPS13A
A2ML1
ANKRD1
CAV3
CHKB
CPT1A
DAG1
EYA4
GNE
NSUN2
POMGNT1
POMT1
POMT2

Test strength

The strengths of this test include:
  • CAP and ISO-15189 accreditations covering all operations at Blueprint Genetics including all Whole Exome Sequencing, NGS panels and confirmatory testing
  • CLIA-certified personnel performing clinical testing in a CLIA-certified laboratory
  • Powerful sequencing technologies, advanced target enrichment methods and precision bioinformatics pipelines ensure superior analytical performance
  • Careful construction of clinically effective and scientifically justified gene panels
  • Our Nucleus online portal providing transparent and easy access to quality and performance data at the patient level
  • Our publically available analytic validation demonstrating complete details of test performance
  • 1479 non-coding disease causing variants in Blueprint WES assay (please see below ‘Non-coding disease causing variants covered by this panel’)
  • Our rigorous variant classification based on modified ACMG variant classification scheme
  • Our systematic clinical interpretation workflow using proprietary software enabling accurate and traceable processing of NGS data
  • Our comprehensive clinical statements

Test limitations

The following exons are not included in the panel as they are not sufficiently covered with high quality sequence reads: *PPA2* (11, 12), *PRKAG2* (10, 13), *RASA2* (3, 6, 17, 19, 20). Genes with suboptimal coverage in our assay are marked with number sign (#) and genes with partial, or whole gene, segmental duplications in the human genome are marked with an asterisk (*) if they overlap with the UCSC pseudogene regions. Gene is considered to have suboptimal coverage when >90% of the gene’s target nucleotides are not covered at >20x with mapping quality score (MQ>20) reads. The technology may have limited sensitivity to detect variants in genes marked with these symbols (please see the Panel content table above).

This test does not detect the following:
  • Complex inversions
  • Gene conversions
  • Balanced translocations
  • Mitochondrial DNA variants
  • Repeat expansion disorders unless specifically mentioned
  • Non-coding variants deeper than ±20 base pairs from exon-intron boundary unless otherwise indicated (please see above Panel Content / non-coding variants covered by the panel).

This test may not reliably detect the following:

  • Low level mosaicism
  • Stretches of mononucleotide repeats
  • Indels larger than 50bp
  • Single exon deletions or duplications
  • Variants within pseudogene regions/duplicated segments

The sensitivity of this test may be reduced if DNA is extracted by a laboratory other than Blueprint Genetics.

For additional information, please refer to the Test performance section and see our Analytic Validation.

The Blueprint Genetics cardiomyopathy panel covers classical genes associated with unspecified arrhythmia, RCM, cardiomyopathy NAS, cardiomegaly, Noonan syndrome, hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), left ventricular non-compaction cardiomyopathy (LVNC) and endocardial fibroelastosis. The genes on the panel have been carefully selected based on scientific literature, mutation databases and our experience.

Our panels are sliced from our high-quality whole exome sequencing data. Please see our sequencing and detection performance table for different types of alterations at the whole exome level (Table).

Assays have been validated for different starting materials including EDTA-blood, isolated DNA (no FFPE), saliva and dry blood spots (filter card) and all provide high-quality results. The diagnostic yield varies substantially depending on the assay used, referring healthcare professional, hospital and country. Blueprint Genetics’ Plus Analysis (Seq+Del/Dup) maximizes the chance to find a molecular genetic diagnosis for your patient although Sequence Analysis or Del/Dup Analysis may be a cost-effective first line test if your patient’s phenotype is suggestive of a specific mutation type.

Performance of Blueprint Genetics Whole Exome Sequencing (WES) assay. All individual panels are sliced from WES data.

Sensitivity % (TP/(TP+FN) Specificity %
Single nucleotide variants 99.65% (412,456/413,893) >99.99%
Insertions, deletions and indels by sequence analysis
1-10 bps 96.94% (17,070/17,608) >99.99%
11-50 bps 99.07% (957/966) >99.99%
Copy number variants (exon level dels/dups)
Clinical samples (small CNVs, n=52)
1 exon level deletion 92.3% (24/26) NA
2 exons level deletion/duplication 100.0% (11/11) NA
3-7 exons level deletion/duplication 93.3% (14/15) NA
Microdeletion/-duplication sdrs (large CNVs, n=37))
Size range (0.1-47 Mb) 100% (37/37)
Simulated CNV detection
2 exons level deletion/duplication 90.98% (7,357/8,086) 99.96%
5 exons level deletion/duplication 98.63% (7,975/8,086) 99.98%
     
The performance presented above reached by WES with the following coverage metrics
     
Mean sequencing depth at exome level 174x
Nucleotides with >20x sequencing coverage (%) 99.4%

Bioinformatics

The target region for each gene includes coding exons and ±20 base pairs from the exon-intron boundary. In addition, the panel includes non-coding variants if listed above (Non-coding variants covered by the panel). Some regions of the gene(s) may be removed from the panel if specifically mentioned in the ‘Test limitations” section above. The sequencing data generated in our laboratory is analyzed with our proprietary data analysis and annotation pipeline, integrating state-of-the art algorithms and industry-standard software solutions. Incorporation of rigorous quality control steps throughout the workflow of the pipeline ensures the consistency, validity and accuracy of results. Our pipeline is streamlined to maximize sensitivity without sacrificing specificity. We have incorporated a number of reference population databases and mutation databases such as, but not limited, to 1000 Genomes Project, gnomAD, ClinVar and HGMD into our clinical interpretation software to make the process effective and efficient. For missense variants, in silico variant prediction tools such as SIFT, PolyPhen, MutationTaster are used to assist with variant classification. Through our online ordering and statement reporting system, Nucleus, the customer has an access to details of the analysis, including patient specific sequencing metrics, a gene level coverage plot and a list of regions with inadequate coverage if present. This reflects our mission to build fully transparent diagnostics where customers have easy access to crucial details of the analysis process.

Clinical interpretation

We provide customers with the most comprehensive clinical report available on the market. Clinical interpretation requires a fundamental understanding of clinical genetics and genetic principles. At Blueprint Genetics, our PhD molecular geneticists, medical geneticists and clinical consultants prepare the clinical statement together by evaluating the identified variants in the context of the phenotypic information provided in the requisition form. Our goal is to provide clinically meaningful statements that are understandable for all medical professionals regardless of whether they have formal training in genetics.

Variant classification is the corner stone of clinical interpretation and resulting patient management decisions. Our classifications follow the Blueprint Genetics Variant Classification Schemes based on the ACMG guideline 2015. Minor modifications were made to increase reproducibility of the variant classification and improve the clinical validity of the report. Our experience with tens of thousands of clinical cases analyzed at our laboratory allowed us to further develop the industry standard.

The final step in the analysis of sequence variants is confirmation of variants classified as pathogenic or likely pathogenic using bi-directional Sanger sequencing. Variant(s) fulfilling all of the following criteria are not Sanger confirmed: 1) the variant quality score is above the internal threshold for a true positive call, 2) an unambiguous IGV in-line with the variant call and 3) previous Sanger confirmation of the same variant at least three times at Blueprint Genetics. Reported variants of uncertain significance are confirmed with bi-directional Sanger sequencing only if the quality score is below our internally defined quality score for true positive call. Reported copy number variations with a size <10 exons are confirmed by orthogonal methods such as qPCR if the specific CNV has been seen less than three times at Blueprint Genetics.

Our clinical statement includes tables for sequencing and copy number variants that include basic variant information (genomic coordinates, HGVS nomenclature, zygosity, allele frequencies, in silico predictions, OMIM phenotypes and classification of the variant). In addition, the statement includes detailed descriptions of the variant, gene and phenotype(s) including the role of the specific gene in human disease, the mutation profile, information about the gene’s variation in population cohorts and detailed information about related phenotypes. We also provide links to the references used, congress abstracts and mutation databases to help our customers further evaluate the reported findings if desired. The conclusion summarizes all of the existing information and provides our rationale for the classification of the variant.

Identification of pathogenic or likely pathogenic variants in dominant disorders or their combinations in different alleles in recessive disorders are considered molecular confirmation of the clinical diagnosis. In these cases, family member testing can be used for risk stratification within the family. In the case of variants of uncertain significance (VUS), we do not recommend family member risk stratification based on the VUS result. Furthermore, in the case of VUS, we do not recommend the use of genetic information in patient management or genetic counseling. For eligible cases, Blueprint Genetics offers a no charge service to investigate the role of reported VUS (VUS Clarification Service).

Our interpretation team analyzes millions of variants from thousands of individuals with rare diseases. Thus, our database, and our understanding of variants and related phenotypes, is growing by leaps and bounds. Our laboratory is therefore well positioned to re-classify previously reported variants as new information becomes available. If a variant previously reported by Blueprint Genetics is re-classified, our laboratory will issue a follow-up statement to the original ordering health care provider at no additional cost.