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Parkinson Disease and Parkinsonism Sequencing Panel with CNV Detection

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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TEST METHODS

Sequencing with CNV

Test Code Test Copy GenesCPT Code Copy CPT Codes
10623 ADORA1 81479,81479 Add to Order
APP 81406,81479
ATP13A2 81479,81479
ATP1A3 81479,81479
ATP6AP2 81479,81479
C19orf12 81479,81479
CHCHD10 81479,81479
CHCHD2 81479,81479
CLN3 81479,81479
CP 81479,81479
CSF1R 81479,81479
DCAF17 81479,81479
DCTN1 81479,81479
DNAJB2 81479,81479
DNAJC12 81479,81479
DNAJC13 81479,81479
DNAJC6 81479,81479
DNM1L 81479,81479
EIF4G1 81479,81479
FBXO7 81479,81479
FTL 81479,81479
GBA 81479,81479
GCH1 81405,81479
GIGYF2 81479,81479
GRN 81406,81479
HTRA2 81479,81479
KIF5A 81479,81479
LRRK2 81408,81479
LYST 81479,81479
MAPT 81406,81479
PARK7 81479,81479
PDE10A 81479,81479
PDE8B 81479,81479
PDGFB 81479,81479
PDGFRB 81479,81479
PINK1 81405,81479
PLA2G6 81479,81479
PODXL 81479,81479
POLG 81406,81479
POLG2 81479,81479
PRKAR1B 81479,81479
PRKN 81479,81479
PRKRA 81479,81479
PRNP 81479,81479
PSEN1 81405,81479
PSEN2 81406,81479
PTRHD1 81479,81479
RAB29 81479,81479
RAB39B 81479,81479
SLC20A2 81479,81479
SLC30A10 81479,81479
SLC39A14 81479,81479
SLC6A3 81479,81479
SNCA 81479,81479
SNCB 81479,81479
SPG11 81407,81479
SPR 81479,81479
SYNJ1 81479,81479
TAF1 81479,81479
TARDBP 81405,81479
TENM4 81479,81479
TH 81406,81479
TWNK 81404,81479
UCHL1 81479,81479
VPS13C 81479,81479
VPS35 81479,81479
WDR45 81479,81479
XPR1 81479,81479
Full Panel Price* $990
Test Code Test Copy Genes Total Price CPT Codes Copy CPT Codes
10623 Genes x (68) $990 81404, 81405(x4), 81406(x6), 81407, 81408, 81479(x123) Add to Order
Pricing Comments

We are happy to accommodate requests for testing single genes in this panel or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available. Alternatively, a single gene or subset of genes can also be ordered via our PGxome Custom Panel tool.

Targeted Testing

For ordering sequencing of targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 26 days.

Clinical Sensitivity

Up to 40% of Parkinson disease patients with age at onset of less than 30 years and 17% of those with age at onset of less than 50 years harbor a pathogenic variant in one of the known monogenic genes linked to Parkinson disease. Within these genes, pathogenic variants in PRKN and LRRK2 are the leading causes of Parkinson disease (Clarimón and Kulisevsky. 2013. PubMed ID: 24532987).

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Clinical Features

Parkinsonism refers to all clinical conditions characterized by tremor, muscle rigidity, bradykinesia and postural instability. Parkinson disease is the primary and most common form of Parkinsonism.

Parkinson disease affects more than 1% of 55-year-olds and more than 3% of those older than age 75 years. Males are more likely to be affected than females. The most common onset for Parkinson disease is around age 60. However, the juvenile form can have onset before 20 years of age. Early onset form is ≤ 50 years of age, while late-onset is after 50 years of age. Within Parkinson disease, only a small fraction of patients (5-10%) are monogenic (Mendelian) inherited (Abeliovich and Gitler. 2016. PubMed ID: 27830778).

The major symptoms of Parkinson's disease include bradykinesia, rigidity, tremor and postural instability. Patients commonly present with a unilateral resting tremor, often described as a pill rolling motion, or bradykinesia, which is a slowness in the execution of movement. As the disease progresses, patients display a stooped posture, shuffling gait, lower limb dystonia and have an increased likelihood of falling. Non-motor features of Parkinson disease include mood disorders, such as depression or anxiety, and sleep disturbance. Dementia may be seen late in Parkinson disease progression manifesting as personality changes and/or memory loss (Beitz. 2014. PubMed ID: 24389262; Abeliovich and Gitler. 2016. PubMed ID: 27830778). The key neuropathology of Parkinson disease is the loss of dopaminergic neurons in the substantia nigra in the midbrain (Beitz. 2014. PubMed ID: 24389262). The hallmark of Parkinson disease in neuropathology is the presence of intraneuronal proteinaceous inclusions, termed Lewy bodies or Lewy neurites (Abeliovich and Gitler. 2016. PubMed ID: 27830778). The presence of Lewy bodies, aggregates of alpha-synuclein, in dopaminergic neurons is variable (Doherty and Hardy. 2013. PubMed ID: 23653422). Patients often respond to treatment with levodopa, a chemical that can cross the blood-brain barrier and be converted into dopamine. Response of motor symptoms to levodopa is also used as evidence to support a Parkinson diagnosis.

Genetics

The genetic etiology of the Parkinson disease and Parkinson related disorders is extremely heterogeneous, ranging from monogenic causes with little or no influence from modifiers or environmental factors to genetically complex forms involving multiple genes, modifier genes and environmental factors (Clarimón and Kulisevsky. 2013. PubMed ID: 24532987; Hernandez et al. 2016. PubMed ID: 27090875; Klein and Schlossmacher. 2007. PubMed ID: 17761553; Abeliovich and Gitler. 2016. PubMed ID: 27830778). Parkinson disease or Parkinsonism related disorders are inherited via autosomal dominant, autosomal recessive, X-linked or complex inheritance. Parkinson diseases or Parkinson related disorders can be sporadic or inherited in families.

The panel covers well-characterized genes causative for Parkinson disease (for example, PRKN, PARK7, PINK1, LRRK2, SNCA, VPS35, DNAJC6 and PLA2G6), as well as many other genes for Parkinsonism related disorders which show overlap phenotype with Parkinson disease (APP, PSEN1, etc.). Certain genes such as GBA and MAPT are susceptibility genes for Parkinson Disease. Recent studies show that the Parkinson disease phenotype is influenced by the severity of the pathogenic variants in the GBA gene (Thaler et al 2018. PubMed ID:29784561; Taguchi et al. 2017. PubMed ID: 28847804).

See individual gene test descriptions for information on molecular biology of gene products and mutation spectra.

Testing Strategy

For this Next Generation Sequencing (NGS) test, sequencing is accomplished by capturing specific regions with an optimized solution-based hybridization kit, followed by massively parallel sequencing of the captured DNA fragments.

For Sanger sequencing, polymerase chain reaction (PCR) is used to amplify targeted regions. After purification of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit. PCR products are resolved by electrophoresis on an ABI 3730xl capillary sequencer. In nearly all cases, cycle sequencing is performed separately in both the forward and reverse directions.

Copy number variants (CNVs) are also detected from NGS data. We utilize a CNV calling algorithm that compares mean read depth and distribution for each target in the test sample against multiple matched controls. Neighboring target read depth and distribution and zygosity of any variants within each target region are used to reinforce CNV calls. All CNVs are confirmed using another technology such as aCGH, MLPA, or PCR before they are reported.

This panel typically provides ≥98% coverage of all coding exons of the genes listed, plus ~10 bases of flanking noncoding DNA. We define coverage as ≥20X NGS reads or Sanger sequencing.

Genes without full coverage: ATP6AP2, CHCHD10, CHCHD2, DNAJC12, DNM1L, GIGYF2, LRRK2, LYST, PDE10A, PINK1, SLC39A14, SYNJ1, TAF1, TENM4, VPS13C. A full list of regions not covered by NGS or Sanger sequencing is available upon request.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Indications for Test

Patients with symptoms suggestive of Parkinson disease are recommended.

Diseases

Name Inheritance OMIM ID
Aceruloplasminemia AR 604290
Alzheimer Disease, Type 3 AD 607822
Alzheimer Disease, Type 4 AD 606889
Alzheimer's Disease AD 104300
Amyotrophic Lateral Sclerosis Type 10 AD 612069
Basal Ganglia Calcification, Idiopathic, 1 AD 213600
Basal Ganglia Calcification, Idiopathic, 4 AD 615007
Basal Ganglia Calcification, Idiopathic, 5 AD 615483
Basal Ganglia Calcification, Idiopathic, 6 AD 616413
Ceroid Lipofuscinosis Neuronal 12 AR 606693
Ceroid Lipofuscinosis Neuronal 3 AR 204200
Chediak-Higashi Syndrome AR 214500
Dystonia 12 AD 128235
Dystonia 16 AR 612067
Dystonia 3, Torsion, X-Linked XLR 314250
Dystonia 5, Dopa-Responsive Type AD 128230
Essential tremor, hereditary, 5 AD 616736
Frontotemporal Dementia AD 600274
Frontotemporal dementia and/or amyotrophic lateral sclerosis 2 AD 615911
Frontotemporal Dementia, Ubiquitin-Positive AD 607485
Gerstmann-Straussler-Scheinker Syndrome AD 137440
Hypermanganesemia with dystonia 1 AR 613280
Hypermanganesemia with dystonia 2 AR 617013
Hyperphenylalaninemia, Mild, Non-BH4-Deficient AR 617384
Infantile Parkinsonism-Dystonia AR 613135
Leukoencephalopathy, Diffuse Hereditary, with Spheroids AD 221820
Lewy Body Dementia AD 127750
Neurodegeneration With Brain Iron Accumulation 4 AR 614298
Neurodegeneration With Brain Iron Accumulation 5 XLD 300894
Neuroferritinopathy AD 606159
Optic atrophy 5 AD 610708
Parkinson Disease 1 AD 168601
Parkinson Disease 11 607688
Parkinson Disease 13 AR 610297
Parkinson Disease 14 AR 612953
Parkinson Disease 15 AR 260300
Parkinson Disease 17 AD 614203
Parkinson Disease 18 AD 614251
Parkinson Disease 19 AR 615528
Parkinson Disease 2 AR 600116
Parkinson Disease 20 AR 615530
Parkinson disease 22, autosomal dominant AD 616710
Parkinson disease 23, autosomal recessive, early onset AR 616840
Parkinson Disease 4 AD 605543
Parkinson Disease 5 613643
Parkinson Disease 6, Autosomal Recessive Early-Onset AR 605909
Parkinson Disease 7 AR 606324
Parkinson Disease 8 AD 607060
Parkinsonism with Spasticity, X-Linked XLR 300911
Perry Syndrome AD 168605
Progressive External Ophthalmoplegia With Mitochondrial DNA Deletions, Autosomal Dominant, 3 AD 609286
Progressive External Ophthalmoplegia With Mitochondrial DNA Deletions, Autosomal Dominant, 4 AD 610131
Sensory Ataxic Neuropathy, Dysarthria, And Ophthalmoparesis AR 607459
Sepiapterin Reductase Deficiency AR 612716
Spastic Paraplegia 10 AD 604187
Spastic Paraplegia 11 AR 604360
Spastic Paraplegia 43 AR 615043
Spastic Paraplegia 78 AR 617225
Spastic Paraplegia 79 AR 615491
Spinal Muscular Atrophy, Distal, Autosomal Recessive, 5 AR 614881
Striatal Degeneration, Autosomal Dominant AD 609161
Striatal degeneration, autosomal dominant AD 616922
Tyrosine Hydroxylase Deficiency AR 605407
Waisman Syndrome XLR 311510
Woodhouse-Sakati Syndrome AR 241080

Related Test

Name
Alzheimer Disease, Familial, Sequencing Panel with CNV Detection

CONTACTS

Genetic Counselors
Geneticist
Citations
  • Abeliovich and Gitler 2016. PubMed ID: 27830778
  • Beitz. 2014. PubMed ID: 24389262
  • Clarimón and Kulisevsky. 2013. PubMed ID: 24532987
  • Doherty and Hardy. 2013. PubMed ID: 23653422
  • Hernandez et al. 2016. PubMed ID: 27090875
  • Klein and Schlossmacher. 2007. PubMed ID: 17761553
  • Taguchi et al. 2017. PubMed ID: 28847804
  • Thaler et al. 2018. PubMed ID: 29784561
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TEST METHODS

Exome Sequencing with CNV Detection

Test Procedure

For the PGxome we use Next Generation Sequencing (NGS) technologies to cover the coding regions of targeted genes plus ~10 bases of non-coding DNA flanking each exon. As required, genomic DNA is extracted from patient specimens. Patient DNA corresponding to these regions is captured using Agilent Clinical Research Exome hybridization probes. Captured DNA is sequenced on the NovaSeq 6000 using 2x150 bp paired-end reads (Illumina, San Diego, CA, USA). The following quality control metrics are generally achieved: >97% of target bases are covered at >20x, and mean coverage of target bases >120x. Data analysis and interpretation is performed by the internally developed software Titanium-Exome. In brief, the output data from the NovaSeq 6000 is converted to fastqs by Illumina Bcl2Fastq, and mapped by BWA. Variant calls are made by the GATK Haplotype caller and annotated using in house software and SnpEff. Variants are filtered and annotated using VarSeq (www.goldenhelix.com).

For Sanger sequencing, polymerase chain reaction (PCR) is used to amplify targeted regions. After purification of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit. PCR products are resolved by electrophoresis on an ABI 3730xl capillary sequencer. In nearly all cases, cycle sequencing is performed separately in both the forward and reverse directions.

Copy number variants (CNVs) are also detected from NGS data. We utilize a CNV calling algorithm that compares mean read depth and distribution for each target in the test sample against multiple matched controls. Neighboring target read depth and distribution and zygosity of any variants within each target region are used to reinforce CNV calls. All CNVs are confirmed using another technology such as aCGH, MLPA, or PCR before they are reported.

Analytical Validity

NextGen Sequencing: As of March 2016, 6.36 Mb of sequence (83 genes, 1557 exons) generated in our lab was compared between Sanger and NextGen methodologies. We detected no differences between the two methods. The comparison involved 6400 total sequence variants (differences from the reference sequences). Of these, 6144 were nucleotide substitutions and 256 were insertions or deletions. About 65% of the variants were heterozygous and 35% homozygous. The insertions and deletions ranged in length from 1 to over 100 nucleotides.

In silico validation of insertions and deletions in 20 replicates of 5 genes was also performed. The validation included insertions and deletions of lengths between 1 and 100 nucleotides. Insertions tested in silico: 2200 between 1 and 5 nucleotides, 625 between 6 and 10 nucleotides, 29 between 11 and 20 nucleotides, 25 between 21 and 49 nucleotides, and 23 at or greater than 50 nucleotides, with the largest at 98 nucleotides. All insertions were detected. Deletions tested in silico: 1813 between 1 and 5 nucleotides, 97 between 6 and 10 nucleotides, 32 between 11 and 20 nucleotides, 20 between 21 and 49 nucleotides, and 39 at or greater than 50 nucleotides, with the largest at 96 nucleotides. All deletions less than 50 nucleotides in length were detected, 13 greater than 50 nucleotides in length were missed. Our standard NextGen sequence variant calling algorithms are generally not capable of detecting insertions (duplications) or heterozygous deletions greater than 100 nucleotides. Large homozygous deletions appear to be detectable.

Copy Number Variant Analysis: The PGxome test detects most larger deletions and duplications including intragenic CNVs and large cytogenetic events; however aberrations in a small percentage of regions may not be accurately detected due to sequence paralogy (e.g., pseudogenes, segmental duplications), sequence properties, deletion/duplication size (e.g., 1-3 exons vs. 4 or more exons), and inadequate coverage. In general, sensitivity for single, double, or triple exon CNVs is ~70% and for CNVs of four exon size or larger is >95%, but may vary from gene-to-gene based on exon size, depth of coverage, and characteristics of the region.

Analytical Limitations

Interpretation of the test results is limited by the information that is currently available. Better interpretation should be possible in the future as more data and knowledge about human genetics and this specific disorder are accumulated.

When sequencing does not reveal any heterozygous differences from the reference sequence, we cannot be certain that we were able to detect both patient alleles.

For technical reasons, the PGxome test is not 100% sensitive. Some exons cannot be efficiently captured, and some genes cannot be accurately sequenced because of the presence of multiple copies in the genome. Therefore, a small fraction of sequence variants will not be detected.

We sequence coding exons for most given transcripts, plus ~10 bp of flanking non-coding DNA for each exon. Unless specifically indicated, test reports contain no information about other portions of the gene, such as regulatory domains, deep intronic regions, uncharacterized alternative exons, chromosomal rearrangements, repeat expansions, epigenetic effects, and mitochondrial genome variants.

In most cases, we are unable to determine the phase of sequence variants. In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants due to somatic mosaicism is limited. Sequence variants that are present in less than 50% of the patient's nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during amplification.

Unless otherwise indicated, DNA sequence data is obtained from a specific cell-type (usually leukocytes if taken from whole blood). Test reports contain no information about the DNA sequence in other cell-types.

We cannot be certain that the reference sequences are correct.

Balanced translocations or inversions are only rarely detected.

Certain types of sex chromosome aneuploidy may not be detected.  

Our ability to detect CNVs due to somatic mosaicism is limited.

We have confidence in our ability to track a specimen once it has been received by PreventionGenetics. However, we take no responsibility for any specimen labeling errors that occur before the sample arrives at PreventionGenetics.

A negative finding does not rule out a genetic diagnosis.

Genetic counseling to help to explain test results to the patients and to discuss reproductive options is recommended.

Order Kits

Ordering Options


myPrevent - Online Ordering
  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
REQUISITION FORM
  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

SPECIMEN TYPES
WHOLE BLOOD

(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.

DNA

(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.

CELL CULTURE

(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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