Tyrosinemia Type III and Hawkinsinuria via the HPD 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
1084 HPD$750.00 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

Clinical sensitivity is difficult to estimate because only a small number of patients have been reported. However, all reported patients with biochemical and enzymatic results consistent with tyrosinemia type III have been found to have two suspected pathogenic sequence variants in the HPD gene (Rüetschi et al. 2000; Tomoeda et al. 2000; Item et al. 2007). All reported Hawkinsinuria patients that have undergone molecular genetic testing have been found to have one suspected pathogenic HPD variant, though there is some controversy in the literature about which variants may actually be causative for Hawkinsinuria (Tomoeda et al. 2000; Item et al. 2007; Gomez-Ospina et al. 2016; Thodi et al. 2016). Overall, these results suggest that the clinical sensitivity of this test is high.

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Deletion/Duplication Testing via aCGH

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

The great majority of tests are completed within 28 days.

Clinical Sensitivity

To date, no gross deletions or duplications have been reported involving the HPD gene (Human Gene Mutation Database).

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Clinical Features

Both tyrosinemia type III and Hawkinsinuria are rare inborn errors of tyrosine metabolism caused by defects in the HPD gene (Mitchell et al. 2014). The onset for both disorders is in infancy.

Very few patients have been reported with tyrosinemia type III, and thus far a consistent clinical picture has not emerged for this disorder. However, the symptoms most commonly reported in affected patients have been ataxia, developmental delay, intellectual disability and behavior abnormalities (Rüetschi et al. 2000; Tomoeda et al. 2000; Item et al. 2007; Mitchell et al. 2014). Biochemically, patients diagnosed with tyrosinemia type III have elevated plasma tyrosine levels and elevated levels of other related metabolites (specifically 4-hydroxyphenylpyruvate, 4-hydroxyphenyllactate and 4-hydroxyphenylacetate) (Rüetschi et al. 2000). Dietary treatment has been somewhat helpful in controlling tyrosine levels in several patients. One patient who was diagnosed based on newborn screening results has been reported. Dietary treatment measures were initiated upon the switch from breastfeeding to formula when the patient was 4 months old. At 30 months of age his psychomotor development was reportedly normal (Heylen et al. 2012). Tyrosinemia type III can be distinguished from types I and II based on the lack of succinylacetone in the urine as well as by differing clinical features. For example, no patients with tyrosinemia type III have been reported to have the ocular or skin symptoms that appear in tyrosinemia type II patients (Rüetschi et al. 2000).

Patients diagnosed with Hawkinsinuria have been reported to undergo growth arrest after weaning from breastfeeding or upon beginning formula feeding. Biochemically, patients exhibit elevated plasma tyrosine levels, persistent metabolic acidosis, and urinary excretion of the same metabolites as tyrosinemia type III patients (4-hydroxyphenylpyruvate, 4-hydroxyphenyllactate and 4-hydroxyphenylacetate). In addition, a compound termed hawkinsin (2-L-cystein-S-yl-1,4-dihydroxycyclohex-5-en-1-yl acetic acid) is always found in the urine and is diagnostic for the disorder (Tomoeda et al. 2000; Item et al. 2007; Gomez-Ospina et al. 2016; Thodi et al. 2016). Clinical symptoms spontaneously resolved at approximately 12 months in all but two reported patients, though patients apparently excrete Hawkinsin in their urine throughout their life (Tomoeda et al. 2000; Gomez-Ospina et al. 2016).


Both tyrosinemia type III and Hawkinsinuria are caused by defects in the HPD gene, which is located on chromosome 12 at 12q24.31. Tyrosinemia type III is an autosomal recessive disorder whereas Hawkinsinuria is an autosomal dominant disorder. To date, fewer than 10 pathogenic variants have been reported in the HPD gene. The majority of the reported variants are missense changes, though a few nonsense and splice variants have also been reported (Human Gene Mutation Database). Only one variant (Ile335Met) has been reported in more than one tyrosinemia type III family; the remaining families with tyrosinemia type III members have had private pathogenic variants. In contrast, Hawkinsinuria is thought to be caused by very specific variants that lead to a partial enzyme defect. It was initially believed that the Ala33Thr variant was the only variant causative for Hawkinsinuria. However, recent reports have suggested that this variant is a benign polymorphism, and that the Asn241Ser variant is more likely a true causative variant for Hawkinsinuria (Gomez-Ospina et al. 2016).

The HPD gene encodes the enzyme 4HPPD (4-hydroxyphenylpyruvic acid dioxygenase). This enzyme is part of the phenylanine and tyrosine catabolic pathway, and is responsible for the conversion of 4-hydroxyphenylpyruvic acid to homogentisic acid (Mitchell et al. 2014).

Testing Strategy

This test involves bidirectional Sanger sequencing using genomic DNA of all coding exons of the HPD gene plus ~20 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 pathogenic variants or to confirm research results.

Indications for Test

Patients with positive newborn screen results showing elevated tyrosine but normal levels of succinylacetone may be good candidates for this test. In addition, patients with clinical and biochemical features consistent with tyrosinemia type III or Hawkinsinuria are good candidates. Family members of patients who have known HPD mutations are also good candidates. We will also sequence the HPD gene to determine carrier status.


Official Gene Symbol OMIM ID
HPD 609695
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Hawkinsinuria AD 140350
Tyrosinemia, Type III AR 276710

Related Test

Autism Spectrum Disorders and Intellectual Disability (ASD-ID) Comprehensive Panel


Genetic Counselors
  • Gomez-Ospina N. et al. 2016. Journal of Inherited Metabolic Disease. 39: 821-829. PubMed ID: 27488560
  • Heylen E. et al. 2012. Molecular Genetics and Metabolism. 107: 605-7. PubMed ID: 23036342
  • Human Gene Mutation Database (Bio-base).
  • Item C.B. et al. 2007. Molecular Genetics and Metabolism. 91: 379-83. PubMed ID: 17560158
  • Mitchell G.A. et al. 2014. Hypertyrosinemia. In: Valle D, Beaudet A.L., Vogelstein B, et al., editors. New York, NY: McGraw-Hill. OMMBID.
  • Rüetschi U. et al. 2000. Human Genetics. 106: 654-62. PubMed ID: 10942115
  • Thodi G. et al. 2016. Journal of Pediatric Endocrinology & Metabolism. 29: 15-20. PubMed ID: 26226126
  • Tomoeda K. et al. 2000. Molecular Genetics and Metabolism. 71: 506-10. PubMed ID: 11073718
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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 20 bases of non-coding DNA flanking the exon are sequenced.

Analytical Validity

As of March 2016, we compared 17.37 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 12 years of our lab operation we have Sanger sequenced roughly 8,800 PCR amplicons. Only one error has been identified, and this was due to sequence analysis error.

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 20 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.

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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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