6-Pyruvoyltetrahydropterin Syntase (PTPS) Deficiency via the PTS 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
1868 PTS$650.00 81479 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

In a total of 19 patients from different families with a clinical diagnosis of 6-pyruvoyltetrahydropterin syntase (PTPS) deficiency, pathogenic variants were detected by sequencing on 35 out of 38 alleles, suggesting an overall detection rate of ~92% (Leuzzi et al. 2010). Analytical sensitivity should also be high because nearly all reported pathogenic variants thus far are detectable by sequencing.

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Clinical Features

Hyperphenylalaninemias due to tetrahydrobiopterin (BH4) deficiency are a result of a disruption in phenylalanine homeostasis and dopamine and serotonin biosynthesis. These disorders are caused by pathogenic variants in genes encoding enzymes involved in the biosynthesis or regeneration of BH4. The phenylalanine, tyrosine, and tryptophan hydroxylases all require BH4 as a cofactor, and lack of this cofactor results in secondary hyperphenylalaninemia and depletion of the neurotransmitters dopamine and serotonin. Early detection and treatment can reduce or prevent neurologic symptoms (Blau et al. 2014).

The most common of the tetrahydrobiopterin deficiencies is 6-pyruvoyltetrahydropterin syntase (PTPS) deficiency, which accounts for approximately 60% of all BH4 deficiencies (Blau et al. 2014). The phenotype of PTPS deficient patients is classified as severe or mild. The severe form is observed in approximately 80% of patients, and such patients develop neurologic symptoms including psychomotor retardation, delayed development, tonal abnormalities, seizures, and dystonia. Patients may also present with abnormal thermogenesis, microcephaly, swallowing difficulties and hypersalivation (Blau et al. 2014). Biochemically, patients classified with severe PTPS deficiency are found to have abnormal levels of CSF neurotransmitters (Leuzzi et al. 2010; Blau et al. 2014). PTPS deficient patients diagnosed with the mild form are generally found to be neurologically normal and have normal neurotransmitter levels, although transient tonal abnormalities, sleeping difficulties and other neurological problems are occasionally observed (Leuzzi et al. 2010; Blau et al. 2014).  

PTPS deficient patients are usually detected via newborn screening due to hyperphenylalaninemia. To distinguish PTPS deficiency from PAH deficiency and other causes of hyperphenylalaninemia, additional studies must be performed, such as a urinary pterin profile, measurement of DHPR enzyme activity, a BH4 loading test, analysis of pterins, folates and neurotransmitters in CSF, and direct PTPS enzyme activity measurement (Ye et al. 2013; Blau et al. 2014). Early diagnosis and treatment is imperative. The neurological outcome, particularly in patients with severe PTPS deficiency, has been shown to be greatly improved if treatment is started before the second month of life (Leuzzi et al. 2010). A phenylalanine-restricted diet is not sufficient to control symptoms in these patients, and many must also be treated with BH4 and neurotransmitter precursor supplementation, although this does not help all patients (Oppliger et al. 1997; Blau et al. 2014). 


6-Pyruvoyltetrahydropterin syntase deficiency is inherited in an autosomal recessive manner. The PTS gene (chromosome 11q22.3, 6 exons) encodes the PTPS enzyme which is involved in the de novo biosynthesis of tetrahydrobiopterin. More specifically, PTPS converts dihydroneopterin triphosphate to 6-pyruvoyl tetrahydropterin (Blau et al. 2014). To date, over 80 pathogenic variants have been reported in the PTS gene. The majority of causative variants are missense, although nonsense, splicing, small deletions and insertions, and one gross deletion have all been reported (Human Gene Mutation Database). Pathogenic variants are spread evenly along the coding sequence. Other inborn errors of BH4 metabolism can present with a similar clinical course and involve dihydropteridine reductase (QDPR gene), GTP cyclohydrolase I (GCH1 gene), and pterin-4α-carbinalamine dehydratase (PCBD1 gene) (Blau et al. 2014, Trujillano et al. 2014).

Testing Strategy

This test involves bidirectional Sanger sequencing using genomic DNA of all coding exons of the PTS gene plus ~10 bp of flanking non-coding DNA on each side. We will also sequence any single exon (Test #100) or pair of exons (Test #200) in family members of patients with known mutations or to confirm research results.

Indications for Test

Newborn screening indicative of hyperpheylalaninemia. Patients with decreased homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5HIAA) in CSF, increased urinary neopterin and decreased biopterin, and a high neopterin/biopterin ratio are good candidates for this test, as are individuals that exhibit clinical symptoms of tetrahydrobiopterin deficiency and family members of patients known to have PTS variants. We will also sequence the PTS gene to determine carrier status.


Official Gene Symbol OMIM ID
PTS 612719
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
6-Pyruvoyl-Tetrahydropterin Synthase Deficiency 261640

Related Tests

Dihydropteridine Reductase (DHPR) Deficiency via the QDPR Gene
Hyperphenylalaninemia Sequencing Panel
Pterin-4 alpha-Carbinolamine Dehydratase (PCD) Deficiency via the PCBD1 Gene
Sepiapterin Reductase (SR) Deficiency via the SPR Gene


Genetic Counselors
  • Blau al. 2014. Disorders of Tetrahydrobiopterin and Related Biogenic Amines. Online Metabolic & Molecular Bases of Inherited Disease, New York, NY: McGraw-Hill.
  • Human Gene Mutation Database (Bio-base).
  • Leuzzi V. et al. 2010. Clinical Genetics. 77: 249-57.  PubMed ID: 20059486
  • Oppliger T. et al. 1997. Human Mutation. 10: 25-35.  PubMed ID: 9222757
  • Trujillano D. et al. 2014. European Journal of Human Genetics : Ejhg. 22: 528-34. PubMed ID: 23942198
  • Ye J. et al. 2013. Journal of Inherited Metabolic Disease. 36: 893-901.  PubMed ID: 23138986
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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.

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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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