Parkinson Disease Panel

Summary
Is a 82 gene panel that includes assessment of non-coding variants.

In addition, it also includes the maternally inherited mitochondrial genome.
Is ideal for patients with a clinical suspicion of Parkinson disease.

Analysis methods
  • PLUS
Availability
4 weeks
Number of genes
82
Test code
NE1501
Panel tier
Tier 2
CPT Code *
81405 x4, 81406 x6, 81408, 81479, 81460, 81465
* The CPT codes provided are based on AMA guidelines and are for informational purposes only. CPT coding is the sole responsibility of the billing party. Please direct any questions regarding coding to the payer being billed.

Summary

The Blueprint Genetics Parkinson Disease Panel (test code NE1501):

Read about our accreditations, certifications and CE-marked IVD medical devices here.

It can detect the *VPS35* c.1858G>A, p.(Asp620Asn) variant, which is within the pseudogene region and is known to be challenging to detect by NGS technologies.

ICD Codes

Refer to the most current version of ICD-10-CM manual for a complete list of ICD-10 codes.

Sample Requirements

  • Blood (min. 1ml) in an EDTA tube
  • Extracted DNA, min. 2 μg in TE buffer or equivalent
  • Saliva (Please see Sample Requirements for accepted saliva kits)

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

We do not accept DNA samples isolated from formalin-fixed paraffin-embedded (FFPE) tissue. In addition, if the patient is affected with a hematological malignancy, DNA extracted from a non-hematological source (e.g. skin fibroblasts) is strongly recommended.

Please note that, in rare cases, mitochondrial genome (mtDNA) variants may not be detectable in blood or saliva in which case DNA extracted from post-mitotic tissue such as skeletal muscle may be a better option.

Read more about our sample requirements here.

Parkinson disease is the second most common neurodegenerative disorder, after Alzheimer disease. Its diagnosis is based on the clinical findings of tremor, rigidity, and bradykinesia. Psychiatric manifestations, which include depression and visual hallucinations, are common but not uniformly present. Dementia eventually occurs in at least 20% of cases. Mendelian (monogenic) forms of Parkinson disease are found in fewer than 5% of all patients and are inherited in an autosomal dominant, autosomal recessive, or, very rarely, X-linked manner. Mendelian forms of Parkinson disease have an earlier age of disease onset than families with typical, late-onset Parkinson disease. Non-Mendelian Parkinson disease is thought to result from the effects of multiple genes as well as environmental risk factors.

Genes in the Parkinson Disease Panel and their clinical significance

To view complete table content, scroll horizontally.

Gene Associated phenotypes Inheritance ClinVar HGMD
ATP13A2 Parkinson disease (Kufor-Rakeb syndrome) AR 21 40
ATP1A3 Alternating hemiplegia of childhood, Dystonia 12 AD 79 112
ATP7B Wilson disease AR 219 897
C19ORF12 Spastic Paraplegia, Neurodegeneration with brain iron accumulation AR 15 37
CHCHD10 Myopathy, isolated mitochondrial, Frontotemporal dementia and/or amyotrophic lateral sclerosis 2, Spinal muscular atrophy, Jokela type AD 4 26
CHCHD2 Parkinson disease 22, autosomal dominant AD 4 12
CP* Aceruloplasminemia, Hypoceruloplasminemia AR 62 57
CSF1R Leukoencephalopathy, diffuse hereditary, with spheroids AD 56 83
DCTN1 Perry syndrome, Neuropathy, distal hereditary motor AD 10 52
DNAJC12 Hyperphenylalaninemia, mild, non-BH4-deficient, Dystonia, Other hyperphenylalaninemias AR 3 8
DNAJC5 Kufs disease,, Ceroid lipofuscinosis, neuronal 4, Parry AD 2 2
DNAJC6 Juvenile Parkinsonism AR 5 14
FBXO7 Parkinson disease AR 5 15
FTL Hyperferritinemia-cataract syndrome, L-ferritin deficiency, Neurodegeneration with brain iron accumulation AD/AR 21 63
GBA* Gaucher disease AR 84 488
GCH1 Dopa-Responsive Dystonia Hyperphenylalaninemia, BH4-deficient, GTP Cyclohydrolase 1-Deficient Dopa-Responsive Dystonia AD/AR 48 240
GRN Frontotemporal lobar degeneration with TDP43 inclusions, GRN-related, Neuronal ceroid lipofuscinosis AD/AR 43 214
LRRK2 Dementia, Lewy body, Parkinson disease AD 14 123
MAPT Pick disease, Frontotemporal dementia, Parkinson-dementia syndrome, Supranuclear palsy, progressive AD/AR 26 104
MT-ATP6 Neuropathy, ataxia, and retinitis pigmentosa, Leber hereditary optic neuropathy, Ataxia and polyneuropathy, adult-onset, Cardiomyopathy, infantile hypertrophic, Leigh syndrome, Striatonigral degeneration, infantile, mitochondrial Mitochondrial 19
MT-ATP8 Cardiomyopathy, apical hypertrophic, and neuropathy, Cardiomyopathy, infantile hypertrophic Mitochondrial 4
MT-CO1 Myoglobinuria, recurrent, Leber hereditary optic neuropathy, Sideroblastic anemia, Cytochrome C oxidase deficiency, Deafness, mitochondrial Mitochondrial 17
MT-CO2 Cytochrome c oxidase deficiency Mitochondrial 8
MT-CO3 Cytochrome c oxidase deficiency, Leber hereditary optic neuropathy Mitochondrial 9
MT-CYB Mitochondrial 69
MT-ND1 Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes, Leber hereditary optic neuropathy, Leber optic atrophy and dystonia Mitochondrial 21
MT-ND2 Leber hereditary optic neuropathy, Mitochondrial complex I deficiency Mitochondrial 6
MT-ND3 Leber optic atrophy and dystonia, Mitochondrial complex I deficiency Mitochondrial 7
MT-ND4 Leber hereditary optic neuropathy, Leber optic atrophy and dystonia, Mitochondrial complex I deficiency Mitochondrial 11
MT-ND4L Leber hereditary optic neuropathy Mitochondrial 2
MT-ND5 Myoclonic epilepsy with ragged red fibers, Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes, Leber hereditary optic neuropathy, Mitochondrial complex I deficiency Mitochondrial 19
MT-ND6 Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes, Oncocytoma, Leber hereditary optic neuropathy, Leber optic atrophy and dystonia, Mitochondrial complex I deficiency Mitochondrial 16
MT-RNR1 Deafness, mitochondrial Mitochondrial 3
MT-RNR2 Chloramphenicol toxicity/resistance Mitochondrial 2
MT-TA Mitochondrial 4
MT-TC Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes Mitochondrial 3
MT-TD Mitochondrial 1
MT-TE Diabetes-deafness syndrome, Mitochondrial myopathy, infantile, transient, Mitochondrial myopathy with diabetes Mitochondrial 5
MT-TF Myoclonic epilepsy with ragged red fibers, Nephropathy, tubulointerstitial, Encephalopathy, mitochondrial, Epilepsy, mitochondrial, Myopathy, mitochondrial, Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes Mitochondrial 7
MT-TG Mitochondrial 3
MT-TH Mitochondrial 4
MT-TI Mitochondrial 7
MT-TK Myoclonic epilepsy with ragged red fibers, Leigh syndrome Mitochondrial 5
MT-TL1 Cytochrome c oxidase deficiency, Myoclonic epilepsy with ragged red fibers, Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes, Diabetes-deafness syndrome, Cyclic vomiting syndrome, SIDS, susceptibility to Mitochondrial 14
MT-TL2 Mitochondrial multisystemic disorder, Progressive external ophthalmoplegia, Mitochondrial Myopathy, Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes Mitochondrial 5
MT-TM Leigh syndrome, Mitochondrial multisystemic disorder Mitochondrial 1
MT-TN Progressive external ophthalmoplegia, Mitochondrial multisystemic disorder Mitochondrial 3
MT-TP Mitochondrial 2
MT-TQ Mitochondrial multisystemic disorder Mitochondrial 2
MT-TR Encephalopathy, mitochondrial Mitochondrial 2
MT-TS1 Myoclonic epilepsy with ragged red fibers, Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes Mitochondrial 10
MT-TS2 Mitochondrial multisystemic disorder Mitochondrial 2
MT-TT Mitochondrial 5
MT-TV Hypertrophic cardiomyopathy (HCM), Leigh syndrome, Mitochondrial multisystemic disorder, Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes Mitochondrial 3
MT-TW Leigh syndrome, Myopathy, mitochondrial Mitochondrial 8
MT-TY Mitochondrial multisystemic disorder Mitochondrial 4
NUS1* Congenital disorder of glycosylation, type 1aa 4 5
PANK2 Hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration, Neurodegeneration with brain iron accumulation AR 37 181
PARK2 Parkinson disease, juvenile AR 45 432
PARK7 Parkinson disease, early onset AR 10 35
PDE10A Striatal degeneration, autosomal dominant 2, Infantile-onset dyskinesia AD/AR 6 5
PDE8B Pigmented nodular adrenocortical disease, Striatal degeneration, autosomal dominant 1 AD 4 11
PDGFB Basal ganglia calcification, idiopathic, 5 AD 8 19
PDGFRB Basal ganglia calcification, idiopathic, 4, Kosaki overgrowth syndrome, Premature aging syndrome, Penttinen type AD 14 19
PINK1 Parkinson disease, early onset AR 17 136
PLA2G6 Parkinson disease, Neurodegeneration with brain iron accumulation AR 78 175
POLG POLG-related ataxia neuropathy spectrum disorders, Sensory ataxia, dysarthria, and ophthalmoparesis, Alpers syndrome, Progressive external ophthalmoplegia with mitochondrial DNA deletions, Mitochondrial DNA depletion syndrome AD/AR 89 290
PRKRA Dystonia 16 AR 2 9
PSEN1 Dilated cardiomyopathy (DCM), Acne inversa, familial, 3, Dementia, frontotemporal, Pick disease, Alzheimer disease AD 57 306
RAB39B Waisman parkinsonism-mental retardation syndrome, Intellectual developmental disorder XL 6 17
SLC20A2 Basal ganglia calcification, idiopathic, 1 AD 22 71
SLC30A10 Hypermanganesemia with dystonia, polycythemia, and cirrhosis AR 15 22
SLC39A14# Hypermanganesemia with dystonia 2 AD/AR 9 9
SLC6A3 Parkinsonism-dystonia, infantile AR 8 31
SNCA Parkinson disease, Dementia with Lewy bodies AD 7 35
SPR Dystonia, Dopa-responsive, due to sepiapterin reductase deficiency AR 12 23
SYNJ1 Epileptic encephalopathy, early infantile, 53, Parkinson disease 20, early-onset AR 12 25
TH Segawa syndrome, autosomal recessive AR 44 71
VPS13A Choreoacanthocytosis AR 19 115
VPS13C Parkinson disease 23, autosomal recessive, early onset AR 10 9
VPS35* Parkinson disease AD 2 22
XPR1 Basal ganglia calcification, idiopathic, 6 AD 4 6
#

The gene has suboptimal coverage (means <90% of the gene’s target nucleotides are covered at >20x with mapping quality score (MQ>20) reads), and/or the gene has exons listed under Test limitations section that are not included in the panel as they are not sufficiently covered with high quality sequence reads.

*

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

The sensitivity to detect variants may be limited in genes marked with an asterisk (*) or number sign (#). Due to possible limitations these genes may not be available as single gene tests.

Gene refers to the HGNC approved gene symbol; Inheritance refers to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR), mitochondrial (mi), 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 Mitomap databases.

Non-coding variants covered by Parkinson Disease Panel

To view complete table content, scroll horizontally.

Gene Genomic location HG19 HGVS RefSeq RS-number
ATP7B Chr13:52518439 c.3061-12T>A NM_000053.3
ATP7B Chr13:52585551 c.-78A>C NM_000053.3
ATP7B Chr13:52585596 c.-128_-124delAGCCG NM_000053.3
ATP7B Chr13:52585596 c.-123C>A NM_000053.3
ATP7B Chr13:52585606 c.-133A>C NM_000053.3
ATP7B Chr13:52585683 c.-210A>T NM_000053.3
ATP7B Chr13:52585894 NM_000053.3 rs1484840087
ATP7B Chr13:52585897 NM_000053.3
ATP7B Chr13:52585915 c.-442G>A NM_000053.3
CSF1R Chr5:149440654 c.1859-119G>A NM_005211.3
FTL Chr19:49468350 c.-415C>A NM_000146.3
FTL Chr19:49468574 c.-189_-161delGGTCCCGCGGGTCTGTCTCTTGCTTCAAC NM_000146.3
FTL Chr19:49468575 c.-190C>T NM_000146.3
FTL Chr19:49468579 c.-186C>G NM_000146.3
FTL Chr19:49468581 c.-184C>T NM_000146.3
FTL Chr19:49468583 c.-182C>T NM_000146.3
FTL Chr19:49468583 c.-182_-178delCGGGTinsTGGGG NM_000146.3
FTL Chr19:49468586 c.-175_-170delGTCTCT NM_000146.3 rs398124639
FTL Chr19:49468587 c.-178T>G NM_000146.3
FTL Chr19:49468589 c.-176T>C NM_000146.3
FTL Chr19:49468593 c.-168_-165delGCTT NM_000146.3
FTL Chr19:49468594 c.-171C>G NM_000146.3
FTL Chr19:49468597 c.-168G>A/C/T NM_000146.3 rs398124635
FTL Chr19:49468597 c.-168G>C NM_000146.3
FTL Chr19:49468597 c.-168G>T NM_000146.3
FTL Chr19:49468597 c.-168G>A NM_000146.3
FTL Chr19:49468598 c.-167C>T NM_000146.3
FTL Chr19:49468598 c.-167C>A/T NM_000146.3
FTL Chr19:49468598 c.-167C>A NM_000146.3
FTL Chr19:49468599 c.-166T>C NM_000146.3
FTL Chr19:49468601 c.-164C>G NM_000146.3
FTL Chr19:49468601 c.-164C>A/T NM_000146.3 rs398124637
FTL Chr19:49468601 c.-158_-143delTGTTTGGACGGAACAG NM_000146.3
FTL Chr19:49468602 c.-161_-160delCA NM_000146.3
FTL Chr19:49468602 c.-163A>C/G/T NM_000146.3
FTL Chr19:49468602 c.-163A>C NM_000146.3
FTL Chr19:49468602 c.-163A>G NM_000146.3
FTL Chr19:49468602 c.-163A>T NM_000146.3
FTL Chr19:49468603 c.-161delC NM_000146.3
FTL Chr19:49468604 c.-161C>A/G NM_000146.3
FTL Chr19:49468604 c.-161C>T NM_000146.3 rs398124636
FTL Chr19:49468605 c.-160A>G NM_000146.3 rs398124633
FTL Chr19:49468606 c.-159G>C NM_000146.3 rs398124634
FTL Chr19:49468608 c.-157G>A NM_000146.3
FTL Chr19:49468611 c.-154T>G NM_000146.3
FTL Chr19:49468612 c.-153G>A NM_000146.3
FTL Chr19:49468612 c.-153_-152delGGinsCT NM_000146.3
FTL Chr19:49468614 c.-151A>G NM_000146.3
FTL Chr19:49468614 c.-151A>C NM_000146.3
FTL Chr19:49468615 c.-150C>A NM_000146.3
FTL Chr19:49468616 c.-149G>C NM_000146.3 rs398124638
FTL Chr19:49468617 c.-148G>C NM_000146.3
FTL Chr19:49468621 c.-144A>T NM_000146.3
FTL Chr19:49468655 c.-110C>T NM_000146.3
FTL Chr19:49468720 c.-44delT NM_000146.3 rs772029022
GBA Chr1:155205646 c.1225-14_1225-11delTGTCinsAGT NM_000157.3
GBA Chr1:155208109 c.589-12C>G NM_000157.3
GBA Chr1:155211053 c.-150A>G NM_000157.3 rs1232943445
GCH1 Chr14:55369403 c.-22C>T NM_000161.2
GRN Chr17:42422701 c.-9A>G NM_002087.2
GRN Chr17:42422705 c.-8+3A>G NM_002087.2
GRN Chr17:42422705 c.-8+3A>T NM_002087.2 rs63751020
GRN Chr17:42422707 c.-8+5G>C NM_002087.2 rs63750313
MAPT Chr17:44087661 c.1774-15T>C NM_016835.4
MAPT Chr17:44087779 c.1866+11T>C NM_016835.4 rs63751394
MAPT Chr17:44087780 c.1866+12C>T NM_016835.4 rs63750916
MAPT Chr17:44087781 c.1866+13A>G NM_016835.4 rs63750308
MAPT Chr17:44087782 c.1866+14C>T NM_016835.4 rs63750972
MAPT Chr17:44087783 c.1866+15A>C NM_016835.4
MAPT Chr17:44087784 c.1866+16C>T NM_016835.4 rs63751011
MAPT Chr17:44087787 c.1866+19C>G NM_016835.4 rs63750162
PANK2 Chr20:3903981 c.*40G>C NM_153638.2
PARK2 Chr6:163148721 c.-21G>T NM_004562.2
PARK7 Chr1:8021919 c.-24+66C>G NM_007262.4
PSEN1 Chr14:73673071 c.869-23_869-22insTGGAATTTTGTGCTGTTG NM_000021.3
SLC20A2 Chr8:42328683 c.289+937G>A NM_006749.4
SNCA Chr4:90647315 c.*464C>A NM_000345.3 rs183204610
SPR Chr2:73114549 c.-13G>A NM_003124.4 rs750423023
TH Chr11:2187017 c.1198-24T>A NM_199292.2
TH Chr11:2188749 c.738-34G>C NM_199292.2
TH Chr11:2193085 c.-69T>A NM_199292.2
TH Chr11:2193086 c.-70G>A NM_199292.2
TH Chr11:2193087 c.-71C>T NM_199292.2 rs549435434

Test Strengths

It can detect the *VPS35* c.1858G>A, p.(Asp620Asn) variant, which is within the pseudogene region and is known to be challenging to detect by NGS technologies.

The strengths of this test include:

  • CAP 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
  • Some of the panels include the whole mitochondrial genome (please see the Panel Content section)
  • Our Nucleus online portal providing transparent and easy access to quality and performance data at the patient level
  • ~2,000 non-coding disease causing variants in our clinical grade NGS assay for panels (please see ‘Non-coding disease causing variants covered by this panel’ in the Panel Content section)
  • 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: *SLC39A14* (NM_001135154:9). 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
  • Some of the panels include the whole mitochondrial genome but not all (please see the Panel Content section)
  • 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 in nuclear genes (variant with a minor allele fraction of 14.6% is detected with 90% probability)
  • Stretches of mononucleotide repeats
  • Low level heteroplasmy in mtDNA (>90% are detected at 5% level)
  • Indels larger than 50bp
  • Single exon deletions or duplications
  • Variants within pseudogene regions/duplicated segments
  • Some disease causing variants present in mtDNA are not detectable from blood, thus post-mitotic tissue such as skeletal muscle may be required for establishing molecular diagnosis.

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.

The genes on the panel have been carefully selected based on scientific literature, mutation databases and our experience.

Our panels are sectioned from our high-quality, clinical grade NGS assay. Please see our sequencing and detection performance table for details regarding our ability to detect different types of alterations (Table).

Assays have been validated for various sample types including EDTA-blood, isolated DNA (excluding from formalin fixed paraffin embedded tissue), saliva and dry blood spots (filter cards). These sample types were selected in order to maximize the likelihood for high-quality DNA yield. The diagnostic yield varies depending on the assay used, referring healthcare professional, hospital and country. Plus analysis increases the likelihood of finding a genetic diagnosis for your patient, as large deletions and duplications cannot be detected using sequence analysis alone. Blueprint Genetics’ Plus Analysis is a combination of both sequencing and deletion/duplication (copy number variant (CNV)) analysis.

The performance metrics listed below are from an initial validation performed at our main laboratory in Finland. The performance metrics of our laboratory in Marlborough, MA, are equivalent.

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 99.2% (7,745/7,806) >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% (25/25)
     
The performance presented above reached by Blueprint Genetics high-quality, clinical grade NGS sequencing assay with the following coverage metrics
     
Mean sequencing depth 143X
Nucleotides with >20x sequencing coverage (%) 99.86%

Performance of Blueprint Genetics Mitochondrial Sequencing Assay.

Sensitivity % Specificity %
ANALYTIC VALIDATION (NA samples; n=4)
Single nucleotide variants
Heteroplasmic (45-100%) 100.0% (50/50) 100.0%
Heteroplasmic (35-45%) 100.0% (87/87) 100.0%
Heteroplasmic (25-35%) 100.0% (73/73) 100.0%
Heteroplasmic (15-25%) 100.0% (77/77) 100.0%
Heteroplasmic (10-15%) 100.0% (74/74) 100.0%
Heteroplasmic (5-10%) 100.0% (3/3) 100.0%
Heteroplasmic (<5%) 50.0% (2/4) 100.0%
CLINICAL VALIDATION (n=76 samples)
All types
Single nucleotide variants n=2026 SNVs
Heteroplasmic (45-100%) 100.0% (1940/1940) 100.0%
Heteroplasmic (35-45%) 100.0% (4/4) 100.0%
Heteroplasmic (25-35%) 100.0% (3/3) 100.0%
Heteroplasmic (15-25%) 100.0% (3/3) 100.0%
Heteroplasmic (10-15%) 100.0% (9/9) 100.0%
Heteroplasmic (5-10%) 92.3% (12/13) 99.98%
Heteroplasmic (<5%) 88.9% (48/54) 99.93%
Insertions and deletions by sequence analysis n=40 indels
Heteroplasmic (45-100%) 1-10bp 100.0% (32/32) 100.0%
Heteroplasmic (5-45%) 1-10bp 100.0% (3/3) 100.0%
Heteroplasmic (<5%) 1-10bp 100.0% (5/5) 99,997%
SIMULATION DATA /(mitomap mutations)
Insertions, and deletions 1-24 bps by sequence analysis; n=17
Homoplasmic (100%) 1-24bp 100.0% (17/17) 99.98%
Heteroplasmic (50%) 100.0% (17/17) 99.99%
Heteroplasmic (25%) 100.0% (17/17) 100.0%
Heteroplasmic (20%) 100.0% (17/17) 100.0%
Heteroplasmic (15%) 100.0% (17/17) 100.0%
Heteroplasmic (10%) 94.1% (16/17) 100.0%
Heteroplasmic (5%) 94.1% (16/17) 100.0%
Copy number variants (separate artifical mutations; n=1500)
Homoplasmic (100%) 500 bp, 1kb, 5 kb 100.0% 100.0%
Heteroplasmic (50%) 500 bp, 1kb, 5 kb 100.0% 100.0%
Heteroplasmic (30%) 500 bp, 1kb, 5 kb 100.0% 100.0%
Heteroplasmic (20%) 500 bp, 1kb, 5 kb 99.7% 100.0%
Heteroplasmic (10%) 500 bp, 1kb, 5 kb 99.0% 100.0%
The performance presented above reached by following coverage metrics at assay level (n=66)
Mean of medians Median of medians
Mean sequencing depth MQ0 (clinical) 18224X 17366X
Nucleotides with >1000x MQ0 sequencing coverage (%) (clinical) 100%
rho zero cell line (=no mtDNA), mean sequencing depth 12X

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. If the test includes the mitochondrial genome the target region gene list contains the mitochondrial genes. 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 suboptimal coverage (<20X for nuclear genes and <1000X for mtDNA) if applicable. This reflects our mission to build fully transparent diagnostics where ordering providers can easily visualize the crucial details of the analysis process.

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 cornerstone of clinical interpretation and resulting patient management decisions. Our classifications follow the ACMG guideline 2015.

The final step in the analysis is orthogonal confirmation. Sequence and copy number variants classified as pathogenic, likely pathogenic, and variants of uncertain significance (VUS) are confirmed using bi-directional Sanger sequencing or by orthogonal methods such as qPCR/ddPCR when they do not meet our stringent NGS quality metrics for a true positive call.

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 healthcare provider at no additional cost, according to our latest follow-up reporting policy.