Dilated Cardiomyopathy (DCM) Panel

Updated
Summary
  • Is a 86 gene panel that includes assessment of non-coding variants
  • Is ideal for patients with a clinical diagnosis or suspicion of dilated cardiomyopathy.

Analysis methods
  • PLUS
Availability

4 weeks

Number of genes

86

Test code

CA2201

Panel size

Small

CPT codes
81439

Summary

The Blueprint Genetics Dilated Cardiomyopathy (DCM) Panel (test code CA2201):

ICD codes

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

ICD-10 Disease
I42.0 Dilated cardiomyopathy (DCM)

Sample Requirements

  • Blood (min. 1ml) in an EDTA tube
  • Extracted DNA, min. 2 μg in TE buffer or equivalent
  • Saliva (Oragene DNA OG-500 kit/OGD-500 or OG-575 & OGD-575)

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. Read more about our sample requirements here.

DCM is one of the major subtypes of cardiomyopathies. It is typically associated with significant dilation of the cardiac chambers (especially the left ventricle), thinning of the myocardial wall and systolic dysfunction. It is a common cause for heart failure, sudden cardiac death and the most common reason for heart transplantation. During the past decade there have been major breakthroughs in the understanding of the molecular genetics of DCM. Similar to hypertrophic cardiomyopathy, genetic diagnostics is becoming standard in the diagnostic work-up of patients suffering from non-ischemic DCM. Studies from large patient and family cohorts have revealed that classical DCM with end stage heart failure and severe symptoms represents the tip of the iceberg in this disorder. The phenotypic spectrum of DCM is broadening as we are now identifying individuals and family members with DCM mutations but who present with less severe cardiac phenotypes. With the increased knowledge of both the genetic causes of the disease and the broadening phenotype, it is estimated that DCM prevalence may be as high as 1:250.

Genes in the Dilated Cardiomyopathy (DCM) Panel and their clinical significance

Gene Associated phenotypes Inheritance ClinVar HGMD
ABCC6* Pseudoxanthoma elasticum AR 352 377
ABCC9 Atrial fibrillation, Cantu syndrome, Dilated cardiomyopathy (DCM) AD 27 46
ACTA1 Myopathy AD/AR 68 212
ACTC1 Left ventricular noncompaction, Hypertrophic cardiomyopathy (HCM), Cardiomyopathy, restrictive, Atrial septal defect, Dilated cardiomyopathy (DCM) AD 23 63
ACTN2 Hypertrophic cardiomyopathy (HCM), Dilated cardiomyopathy (DCM) AD 11 44
ALMS1* Alström syndrome AR 197 302
ALPK3 Pediatric cardiomyopathy AR 12 6
APOA1 Amyloidosis, systemic nonneuronopathic, Hypoalphalipoproteinemia AD/AR 28 71
BAG3 Dilated cardiomyopathy (DCM), Myopathy, myofibrillar AD 39 62
CASZ1 Dilated cardiomyopathy (DCM), Ventricular septal defect AD 3 2
CHRM2 Dilated cardiomyopathy (DCM) AD/AR 1
DES Dilated cardiomyopathy (DCM), Myopathy, myofibrillar, Scapuloperoneal syndrome, neurogenic, Kaeser type AD/AR 64 124
DMD Becker muscular dystrophy, Duchenne muscular dystrophy, Dilated cardiomyopathy (DCM) XL 832 3915
DOLK Congenital disorder of glycosylation AR 8 11
DPM3 Congenital disorder of glycosylation, Dilated cardiomyopathy (DCM), Limb-girdle muscular dystrophy AR 3 2
DSC2 Arrhythmogenic right ventricular dysplasia with palmoplantar keratoderma and woolly hair, Arrhythmogenic right ventricular dysplasia AD/AR 32 87
DSG2 Arrhythmogenic right ventricular dysplasia, Dilated cardiomyopathy (DCM) AD 44 129
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 177 296
DYSF Miyoshi muscular dystrophy, Muscular dystrophy, limb-girdle, Myopathy, distal, with anterior tibial onset AR 244 529
EEF1A2 Epileptic encephalopathy, early infantile, Mental retardation AD 17 12
EMD Emery-Dreifuss muscular dystrophy XL 48 113
EPG5 Vici syndrome AR 36 66
ETFA Glutaric aciduria, Multiple acyl-CoA dehydrogenase deficiency AR 8 29
ETFB Glutaric aciduria, Multiple acyl-CoA dehydrogenase deficiency AR 6 15
ETFDH Glutaric aciduria, Multiple acyl-CoA dehydrogenase deficiency AR 43 190
FBXO32 Dilated cardiomyopathy (DCM) AD/AR 2
FHOD3 Cardiomyopathy, familial hypertrophic AD 1
FKTN Muscular dystrophy-dystroglycanopathy, Dilated cardiomyopathy (DCM), Muscular dystrophy-dystroglycanopathy (limb-girdle) AD/AR 45 58
FLNC* Myopathy AD 54 109
FOXD4* Dilated cardiomyopathy (DCM) AD 1
GATA4* Tetralogy of Fallot, Atrioventricular septal defect, Testicular anomalies with or without congenital heart disease, Ventricular septal defect, Atrial septal defect AD 37 140
GATA6 Heart defects, congenital, and other congenital anomalies, Atrial septal defect 9, atrioventricular septal defect 5, Persistent truncus arteriosus, Tetralogy of Fallot AD 16 82
GATC* Cardiomyopathy, fatal AR 1
GBE1 Glycogen storage disease AR 36 70
GLB1 GM1-gangliosidosis, Mucopolysaccharidosis (Morquio syndrome) AR 90 220
GSK3B Hypertrophic cardiomyopathy, Dilated cardiomyopathy (DCM) 2
HAND1 Congenital heart defects, Dilated cardiomyopathy AD 9
HCN4 Sick sinus syndrome, Brugada syndrome, Left ventricular non-compaction cardiomyopathy (LVNC) AD 8 34
ILK Dilated cardiomyopathy (DCM) AD/AR 10
JPH2 Hypertrophic cardiomyopathy (HCM) AD 3 13
JUP Arrhythmogenic right ventricular dysplasia, Naxos disease AD/AR 8 46
KLHL24 Epidermolysis bullosa simplex, generalized, with scarring and hair loss, Dilated cardiomyopathy (DCM), Hypertrophic cardiomyopathy (HCM) AD/AR 5 5
LAMP2 Danon disease XL 62 101
LDB3 Dilated cardiomyopathy (DCM), Myopathy, myofibrillar AD 9 14
LEMD2 Cataract 46, juvenile onset, Arrhythmogenic right ventricular cardiomyopathy (ARVC), Dilated cardiomyopathy (DCM) AR 1 1
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 250 564
LMOD2 Familial dilated cardiomyopathy AR
LRRC10 Dilated cardiomyopathy (DCM) AD/AR 4
MLYCD Malonyl-CoA decarboxylase deficiency AR 14 38
MYBPC3 Left ventricular noncompaction, Hypertrophic cardiomyopathy (HCM), Dilated cardiomyopathy (DCM) AD 482 1048
MYBPHL Dilated cardiomyopathy (DCM) AD 3
MYH6 Hypertrophic cardiomyopathy (HCM), Dilated cardiomyopathy (DCM), Atrial septal defect 3 AD 14 123
MYH7 Hypertrophic cardiomyopathy (HCM), Myopathy, myosin storage, Myopathy, distal, Dilated cardiomyopathy (DCM) AD 305 986
MYL4 Atrial fibrillation, familial, 18 AD 2 2
NKX2-5 Conotruncal heart malformations, Hypothyroidism, congenital nongoitrous,, Atrial septal defect, Ventricular septal defect 3, Conotruncal heart malformations, variable, Tetralogy of Fallot AD 45 108
NRAP Dilated cardiomyopathy (DCM) AR 1 6
PCCA Propionic acidemia AR 66 125
PCCB# Propionic acidemia AR 68 115
PKP2#* Arrhythmogenic right ventricular dysplasia AD 150 289
PLEKHM2 Dilated cardiomyopathy (DCM), left ventricular noncompaction AR 1 1
PLN Hypertrophic cardiomyopathy (HCM), Dilated cardiomyopathy (DCM) AD/AR 8 30
PPCS Dilated cardiomyopathy (DCM) AR 4
PRDM16 Left ventricular noncompaction, Dilated cardiomyopathy (DCM) AD 17 20
QRSL1 Mitochondrial multisystemic disorder AR 4 2
RAF1 LEOPARD syndrome, Noonan syndrome, Dilated cardiomyopathy (DCM) AD 45 53
RBCK1 Polyglucosan body myopathy AR 11 14
RBM20 Dilated cardiomyopathy (DCM) AD 19 47
RMND1* Combined oxidative phosphorylation deficiency AR 17 15
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 234 899
SPEG Centronuclear myopathy 5 AR 5 11
TAB2 Congenital heart defects, multiple types, 2 AD 13 31
TAZ 3-Methylglutaconic aciduria, (Barth syndrome) XL 45 158
TBX20* Atrial septal defect 4 AD 4 28
TBX5 Holt-Oram syndrome AD 61 127
TCAP Muscular dystrophy, limb-girdle, Hypertrophic cardiomyopathy (HCM), Dilated cardiomyopathy (DCM) AD/AR 12 28
TMEM43 Arrhythmogenic right ventricular dysplasia, Emery-Dreifuss muscular dystrophy AD 4 24
TNNC1 Hypertrophic cardiomyopathy (HCM), Dilated cardiomyopathy (DCM) AD 9 24
TNNI3 Hypertrophic cardiomyopathy (HCM), Cardiomyopathy, restrictive, Dilated cardiomyopathy (DCM) AD/AR 56 129
TNNI3K Cardiac conduction disease with or without dilated cardiomyopathy AD 1 3
TNNT2 Left ventricular noncompaction, Hypertrophic cardiomyopathy (HCM), Cardiomyopathy, restrictive, Dilated cardiomyopathy (DCM) AD 61 148
TOR1AIP1 Muscular dystrophy with progressive weakness, distal contractures and rigid spine AD/AR 3 5
TPM1 Hypertrophic cardiomyopathy (HCM), Dilated cardiomyopathy (DCM) AD 34 98
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 818 327
TTR Dystransthyretinemic hyperthyroxinemia, Amyloidosis, hereditary, transthyretin-related AD 52 148
VCL Hypertrophic cardiomyopathy (HCM), Dilated cardiomyopathy (DCM) AD 8 30
VPS13A Choreoacanthocytosis AR 19 115

* 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 Dilated Cardiomyopathy (DCM) Panel

Gene Genomic location HG19 HGVS RefSeq RS-number
ABCC6 Chr16:16244424 c.4403+11C>G NM_001171.5 rs72664215
ABCC6 Chr16:16256835 c.3506+15G>A NM_001171.5 rs72664302
ABCC6 Chr16:16281097 c.1780-29T>A NM_001171.5 rs72664206
ABCC6 Chr16:16284246 c.1432-22C>A NM_001171.5 rs72664297
ACTC1 Chr15:35080829 c.*1784T>C NM_005159.4
APOA1 Chr11:116708299 c.-21+22G>A NM_000039.1
APOA1 Chr11:116708365 c.-65A>C NM_000039.1
DMD ChrX:31165653 c.10554-18C>G NM_004006.2
DMD ChrX:31200680 c.9974+175T>A 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:31226400 c.9563+1215A>G NM_004006.2
DMD ChrX:31229031 c.9362-1215A>G NM_004006.2
DMD ChrX:31241047 c.9361+117A>G 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:31279420 c.9225-287C>A 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:31332523 c.9224+9192C>A NM_004006.2
DMD ChrX:31382270 c.9085-15519G>T NM_004006.2
DMD ChrX:31613687 c.8217+32103G>T NM_004006.2
DMD ChrX:31627738 c.8217+18052A>G NM_004006.2
DMD ChrX:31697714 c.7661-11T>C NM_004006.2
DMD ChrX:31897527 c.6913-4037T>G NM_004006.2
DMD ChrX:31983146 c.6614+3310G>T NM_004006.2 rs797045526
DMD ChrX:32274692 c.6290+30954C>T NM_004006.2
DMD ChrX:32305833 c.6118-15A>G NM_004006.2
DMD ChrX:32360414 c.5740-15G>T NM_004006.2
DMD ChrX:32366860 c.5326-215T>G NM_004006.2
DMD ChrX:32379144 c.5325+1743_5325+1760delTATTAAAAAATGGGTAGA NM_004006.2
DMD ChrX:32398808 c.4675-11A>G NM_004006.2
DMD ChrX:32460274 c.3787-843C>A NM_004006.2
DMD ChrX:32470726 c.3603+2053G>C NM_004006.2
DMD ChrX:32479316 c.3432+2240A>G NM_004006.2
DMD ChrX:32479520 c.3432+2036A>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:32716130 c.832-15A>G NM_004006.2 rs72470513
DMD ChrX:32756908 c.650-39498A>G NM_004006.2
DMD ChrX:32827744 c.531-16T>A/G NM_004006.2
DMD ChrX:32827744 c.531-16T>A NM_004006.2
DMD ChrX:32827744 c.531-16T>G NM_004006.2
DMD ChrX:32841967 c.265-463A>G NM_004006.2
DMD ChrX:33032666 c.93+5590T>A NM_004006.2
DMD ChrX:33192452 c.31+36947G>A NM_004006.2
DMD ChrX:33229483 c.-54T>A NM_004006.2
DSC2 Chr18:28683379 c.-1445G>C NM_024422.4 rs75494355
DYSF Chr2:71840553 c.4410+13T>G NM_003494.3
DYSF Chr2:71900503 c.5668-824C>T NM_003494.3
DYSF Chr2:71913729 c.*107T>A NM_003494.3 rs11903223
EMD ChrX:153608559 c.266-27_266-10delTCTGCTACCGCTGCCCCC NM_000117.2
ETFDH Chr4:159593534 c.-75A>G NM_004453.2
ETFDH Chr4:159602711 c.176-636C>G NM_004453.2
FKTN Chr9:108368857 c.648-1243G>T NM_006731.2
GATA4 Chr8:11561282 c.-989C>T NM_002052.3
GATA4 Chr8:11561369 c.-902G>T NM_002052.3
GATA4 Chr8:11561399 NM_002052.3 rs1195641788
GATA4 Chr8:11612500 c.910-55T>C NM_002052.3
GATA4 Chr8:11612745 c.997+103G>T NM_002052.3 rs113049875
GATA4 Chr8:11614418 c.998-26G>A NM_002052.3
GATA6 Chr18:19749151 c.-530A>T NM_005257.4
GATA6 Chr18:19749272 c.-409C>G NM_005257.4
GBE1 Chr3:81542964 c.2053-3358_2053-3350delGTGTGGTGGinsTGTTTTTTACATGACAGGT NM_000158.3 rs869320698
LMNA Chr1:156100609 c.513+45T>G NM_170707.3
LMNA Chr1:156105681 c.937-11C>G NM_170707.3 rs267607645
LMNA Chr1:156107037 c.1608+14G>A NM_170707.3
LMNA Chr1:156107433 c.1609-12T>G NM_170707.3 rs267607582
MLYCD Chr16:83948547 c.949-14A>G NM_012213.2 rs761146008
MYBPC3 Chr11:47353394 c.*26+2T>C NM_000256.3
MYBPC3 Chr11:47353821 c.3628-12C>G NM_000256.3 rs371428751
MYBPC3 Chr11:47359371 c.2309-26A>G NM_000256.3
MYBPC3 Chr11:47360310 c.2149-80G>A NM_000256.3
MYBPC3 Chr11:47364709 c.1227-13G>A NM_000256.3 rs397515893
MYBPC3 Chr11:47364832 c.1224-19G>A NM_000256.3 rs587776699
MYBPC3 Chr11:47364865 c.1224-52G>A NM_000256.3 rs786204336
MYBPC3 Chr11:47365750 c.1091-575A>C NM_000256.3
MYBPC3 Chr11:47367305 c.1090+453C>T NM_000256.3
MYBPC3 Chr11:47368602 c.906-22G>A NM_000256.3 rs756267771
MYBPC3 Chr11:47368616 c.906-36G>A NM_000256.3 rs864622197
NKX2-5 Chr5:172662741 NM_004387.3
NKX2-5 Chr5:172672291 c.-10205G>A .
NKX2-5 Chr5:172672303 c.-10217G>C .
PCCA Chr13:100958030 c.1285-1416A>G NM_000282.3
PCCB Chr3:136003251 c.714+462A>G NM_001178014.1
PLN Chr6:118869382 c.-271A>G NM_002667.4
PLN Chr6:118869417 c.-236C>G NM_002667.4 rs188578681
SCN5A Chr3:38639469 c.2024-11T>A NM_198056.2 rs777987317
SCN5A Chr3:38691021 c.-53+1G>A NM_198056.2
TAZ ChrX:153641699 n.694+4G>A NR_024048.1
TAZ ChrX:153649161 c.778-63_778-51delCTCCCAGGGCACC NM_000116.3 rs782249471
TBX20 Chr7:35293780 c.-549G>A NM_001077653.2 rs571512677
TBX5 Chr12:114704515 c.*88822C>A NM_000192.3 rs141875471
TPM1 Chr15:63349172 c.241-12_241-11delCTinsTG NM_001018005.1 rs199476309

Added and removed genes from the panel

Genes added Genes removed
CASZ1
CHRM2
DPM3
FHOD3
GATA4
GATC
GSK3B
ILK
KLHL24
LDB3
LEMD2
LMOD2
NKX2-5
NRAP
PPCS
QRSL1
TMEM43

Test Strengths

The strengths of this test include:
  • CAP and ISO-15189 accredited laboratory
  • 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 publicly available analytic validation demonstrating complete details of test performance
  • ~2,000 non-coding disease causing variants in our clinical grade NGS assay for panels (please see below ‘Non-coding disease causing variants covered by this panel’)
  • Our rigorous 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: PCCB (NM_001178014:4), PKP2 (NM_001254727:6). 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 (variant with a minor allele fraction of 14.6% is detected with 90% probability)
  • 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 dilated cardiomyopathy (DCM) panel covers classical genes associated with dilated cardiomyopathy (DCM) and cardioegaly. 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 high-quality, clinical grade NGS sequencing assay for panels.

Sensitivity % (TP/(TP+FN) Specificity %
Single nucleotide variants 99.89% (99,153/99,266) >99.9999
Insertions, deletions and indels by sequence analysis
1-10 bps 96.9% (7,563/7,806) >99.9999
11-50 bps 99.13% (2,524/2,546) >99.9999
Copy number variants (exon level dels/dups)
1 exon level deletion (heterozygous) 100% (20/20) NA
1 exon level deletion (homozygous) 100% (5/5) NA
1 exon level deletion (het or homo) 100% (25/25) NA
2-7 exon level deletion (het or homo) 100% (44/44) NA
1-9 exon level duplication (het or homo) 75% (6/8) NA
Simulated CNV detection
5 exons level deletion/duplication 98.7% 100.00%
Microdeletion/-duplication sdrs (large CNVs, n=37))
Size range (0.1-47 Mb) 100% (37/37)
     
The performance presented above reached by WES with the following coverage metrics
     
Mean sequencing depth at exome level 143X
Nucleotides with >20x sequencing coverage (%) 99.86%

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 and regulatory 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 including, 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, ordering providers have access to the details of the analysis, including patient specific sequencing metrics, a gene level coverage plot and a list of regions with <20X sequencing depth if applicable. This reflects our mission to build fully transparent diagnostics where ordering providers can easily visualize the 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 is orthogonal confirmation. Sequence variants classified as pathogenic, likely pathogenic and variants of uncertain significance (VUS) are confirmed using bi-directional Sanger sequencing when they do not meet our stringent NGS quality metrics for a true positive call.
Reported heterozygous and homo/hemizygous copy number variations with a size <10 and <3 target exons are confirmed by orthogonal methods such as qPCR if the specific CNV has been seen and confirmed 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, abstracts and variant databases used to help ordering providers 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. We do not recommend using variants of uncertain significance (VUS) for family member risk stratification or patient management. Genetic counseling is recommended.

Our interpretation team analyzes millions of variants from thousands of individuals with rare diseases. Our internal database and our understanding of variants and related phenotypes increases with every case analyzed. 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.

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