Autosomal Domianant DOPA-Responsive Dystonia via the GCH1 Gene

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
161 GCH1$680.00 81405 Add to Order
Targeted Testing

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

Turnaround Time

The great majority of tests are completed within 18 days.

Clinical Sensitivity

This test will detect pathogenic variants in the GCH1 gene in up to 87% of patients with a clinical diagnosis of dystonia and marked and sustained response to levodopa treatment (Hagenah et al. 2005: Clot et al. 2009).

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Deletion/Duplication Testing via aCGH

Test Code Test Copy GenesIndividual Gene PriceCPT Code Copy CPT Codes
600 GCH1$690.00 81479 Add to Order
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Turnaround Time

The great majority of tests are completed within 28 days.

Clinical Sensitivity

This test will detect large pathogenic deletions involving the GCH1 gene in up to 11% of patients with a clinical diagnosis of dystonia and marked and sustained response to levodopa treatment (Steinberger et al. 2007; Clot et al. 2009).

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Clinical Features

Autosomal Dominant DOPA-Responsive Dystonia (AD-DRD) is characterized by a childhood-onset dystonia that responds well to low doses of oral levodopa. It is a heterogeneous disorder in respect to age of onset, clinical features, and disease progression. Average age of onset is about 6 years. Dystonia of the foot is usually the presenting feature and results in gait disturbance. Patients occasionally present with arm dystonia, hand tremor, or slowness of movements. Additional features include brisk deep-tendon reflexes in the leg, ankle or big toe and spasticity. Symptoms can increase in severity later in the day and/or following physical exertion. They are lessened after a night's sleep (Ichinose et al. 1994; Grimes et al. 2002; Klein et al. 2002). Psychiatric manifestations in the form of depression, anxiety, obsessive compulsive behavior, eating disorders, sleep disorders have been reported in rare cases (Hahn et al. 2001; Van Hove et al. 2006). Localized symptoms often progress gradually to a more generalized dystonia, although dystonic movements are prevalent in the legs during the entire course of the disease. Parkinson-like symptoms in the form of postural tremor, bradykinesia and rigidity may develop at later ages. AD-DRD does not affect life expectancy (Furukawa 2015).

DRD is estimated to affect about 0.5 in 1,000,000 individuals worldwide (Nygaard et al. 1993).


Autosomal dominant DRD is inherited with gender-related incomplete penetrance. The disease is 3-4 times more prevalent in female patients than in males, with no clear evidence for genetic imprinting (Furukawa et al. 1998). An apparently negative family history is reported in a significant number of affected individuals (Cai et al. 2013). It is unclear how many of the apparently sporadic cases are inherited with low penetrance.

Pathogenic variants in the GCH1 gene are the major genetic cause of AD-DRD. About 200 causative variants have been reported to date. All types of variants have been reported. About half of these are missense. The other half is made mostly of truncating variants, including large deletions (Ichinose et al. 1994; Hagenah et al. 2005; Furukawa et al. 2000; Klein et al. 2002; Steinberger et al. 2007). De novo GCH1 pathogenic variants have been reported in patients with AD-DRD, and a relatively high spontaneous mutation rate in the gene has been speculated (Furukawa et al. 1998). Pathogenic variants in GCH1 have been reported in patients with AD-DRD from various geographic and ethnic origins (Bandmann et al. 1996; Steinberger et al. 2000; Ohta et al. 2006; Scola et al. 2007; Camargos et al. 2008).

GCH1 encodes the GTP cyclohydrolase 1 enzyme, which catalyzes the first step of tetrahydrobiopterin synthesis. Tetrahydrobiopterin is a co-factor for the rate-limiting enzyme tyrosine hydroxylase that is involved in the biosynthesis of catecholamines, including dopamine.

Testing Strategy

This test involves PCR amplification from genomic DNA and bidirectional sequencing of all coding exons of the GCH1 gene. The full coding region of each exon plus ~10 bp of flanking non-coding DNA on either side are sequenced. We will also sequence any single exon (Test #100) in family members of patients with a known mutation or to confirm research results.

Indications for Test

Candidates for this test are patients with a clinical diagnosis of dystonia and marked and sustained response to levodopa treatment. Family members of patients with known pathogenic variants are also candidate for this test. In addition to this test, PreventionGenetics also offers sequencing of all of the other known genes that have been conclusively implicated in Dystonia (Klein et al. 2014; Lohmann and Klein 2017).


Official Gene Symbol OMIM ID
GCH1 600225
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Dystonia 5, Dopa-Responsive Type AD 128230

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Genetic Counselors
  • Bandmann O. et al. 1996. Human Molecular Genetics. 5: 403-6. PubMed ID: 8852666
  • Cai C. et al. 2013. Plos One. 8: e65215. PubMed ID: 23762320
  • Camargos S.T. et al. 2008. Movement Disorders. 23: 299-302. PubMed ID: 18044725
  • Clot F. et al. 2009. Brain. 132: 1753-63. PubMed ID: 19491146
  • Furukawa Y. 2015. GTP Cyclohydrolase 1-Deficient Dopa-Responsive Dystonia. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews™, Seattle (WA): University of Washington, Seattle. PubMed ID: 20301681
  • Furukawa Y. et al. 1998. Neurology. 50: 1015-20. PubMed ID: 9566388
  • Furukawa Y. et al. 2000. Annals of Neurology. 47: 517-20. PubMed ID: 10762165
  • Grimes D.A. et al. 2002. Journal of Neurology, Neurosurgery & Psychiatry. 72: 801–804. PubMed ID: 12023430
  • Hagenah J. et al. 2005. Neurology. 64: 908-11. PubMed ID: 15753436
  • Hahn H. et al. 2001. Archives of Neurology. 58: 749-55. PubMed ID: 11346370
  • Ichinose H. et al. 1994. Nature Genetics. 8: 236-42. PubMed ID: 7874165
  • Klein C. et al. 2002. Neurology. 59: 1783–6. PubMed ID: 12473771
  • Klein C. et al. 2014. Dystonia Overview. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews™, Seattle (WA): University of Washington, Seattle. PubMed ID: 20301334
  • Lohmann K., Klein C. 2017. Current Neurology and Neuroscience Reports. 17: 26. PubMed ID: 28283962
  • Nygaard T.G. et al. 1993. Nature Genetics. 5: 386-91. PubMed ID: 8298648
  • Ohta E. et al. 2006. Archives of Neurology. 63: 1605-10. PubMed ID: 17101830
  • Scola R.H. et al. 2007. Arquivos De Neuro-psiquiatria. 65: 1224–7. PubMed ID: 18345435
  • Steinberger D. et al. 2000. Neurology. 55: 1735-7. PubMed ID: 11113234
  • Steinberger D. et al. 2007. Neurogenetics. 8: 51-5. PubMed ID: 17111153
  • Van Hove J.L. et al. 2006. Journal of Neurology, Neurosurgery, and Psychiatry. 77: 18-23. PubMed ID: 16361586
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Bi-Directional Sanger Sequencing

Test Procedure

Nomenclature for sequence variants was from the Human Genome Variation Society (  As required, DNA is extracted from the patient specimen.  PCR is used to amplify the indicated exons plus additional flanking non-coding sequence.  After cleaning of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  Products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In most cases, sequencing is performed in both forward and reverse directions; in some cases, sequencing is performed twice in either the forward or reverse directions.  In nearly all cases, the full coding region of each exon as well as 10 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of February 2018, we compared 26.8 Mb of Sanger DNA sequence generated at PreventionGenetics to NextGen sequence generated in other labs. We detected only 4 errors in our Sanger sequences, and these were all due to allele dropout during PCR. For Proficiency Testing, both external and internal, in the 14 years of our lab operation we have Sanger sequenced roughly 14,300 PCR amplicons. Only one error has been identified, and this was an error in analysis of sequence data.

Our Sanger sequencing is capable of detecting virtually all nucleotide substitutions within the PCR amplicons. Similarly, we detect essentially all heterozygous or homozygous deletions within the amplicons. Homozygous deletions which overlap one or more PCR primer annealing sites are detectable as PCR failure. Heterozygous deletions which overlap one or more PCR primer annealing sites are usually not detected (see Analytical Limitations). All heterozygous insertions within the amplicons up to about 100 nucleotides in length appear to be detectable. Larger heterozygous insertions may not be detected. All homozygous insertions within the amplicons up to about 300 nucleotides in length appear to be detectable. Larger homozygous insertions may masquerade as homozygous deletions (PCR failure).

Analytical Limitations

In exons where our sequencing did not reveal any variation between the two alleles, we cannot be certain that we were able to PCR amplify both of the patient’s alleles. Occasionally, a patient may carry an allele which does not amplify, due for example to a deletion or a large insertion. In these cases, the report contains no information about the second allele.

Similarly, our sequencing tests have almost no power to detect duplications, triplications, etc. of the gene sequences.

In most cases, only the indicated exons and roughly 10 bp of flanking non-coding sequence on each side are analyzed. Test reports contain little or no information about other portions of the gene, including many regulatory regions.

In nearly all 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 for example 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 PCR and cycle sequencing.

Unless otherwise indicated, the sequence data that we report are based on DNA isolated from a specific tissue (usually leukocytes). Test reports contain no information about gene sequences in other tissues.

Deletion/Duplication Testing via Array Comparative Genomic Hybridization

Test Procedure

Equal amounts of genomic DNA from the patient and a gender matched reference sample are amplified and labeled with Cy3 and Cy5 dyes, respectively. To prevent any sample cross contamination, a unique sample tracking control is added into each patient sample. Each labeled patient product is then purified, quantified, and combined with the same amount of reference product. The combined sample is loaded onto the designed array and hybridized for at least 22-42 hours at 65°C. Arrays are then washed and scanned immediately with 2.5 µM resolution. Only data for the gene(s) of interest for each patient are extracted and analyzed.

Analytical Validity

PreventionGenetics' high density gene-centric custom designed aCGH enables the detection of relatively small deletions and duplications within a single exon of a given gene or deletions and duplications encompassing the entire gene. PreventionGenetics has established and verified this test's accuracy and precision.

Analytical Limitations

Our dense probe coverage may allow detection of deletions/duplications down to 100 bp; however due to limitations and probe spacing this cannot be guaranteed across all exons of all genes. Therefore, some copy number changes smaller than 100-300 bp within a targeted large exon may not be detected by our array.

This array may not detect deletions and duplications present at low levels of mosaicism or those present in genes that have pseudogene copies or repeats elsewhere in the genome.

aCGH will not detect balanced translocations, inversions, or point mutations that may be responsible for the clinical phenotype.

Breakpoints, if occurring outside the targeted gene, may be hard to define.

The sensitivity of this assay may be reduced when DNA is extracted by an outside laboratory.

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.
  • 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.


(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.


(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.


(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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