Tyrosinemia Type III and Hawkinsinuria via the HPD Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
8453 HPD 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8453HPD81479 81479 $890 Order Options and Pricing

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information. If the Sanger option is selected, CNV detection may be ordered through Test #600.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

For Reflex to PGxome pricing click here.

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

Turnaround Time

18 days on average for standard orders or 14 days on average for STAT orders.

Once a specimen has started the testing process in our lab, the most accurate prediction of TAT will be displayed in the myPrevent portal as an Estimated Report Date (ERD) range. We calculate the ERD for each specimen as testing progresses; therefore the ERD range may differ from our published average TAT. View more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

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).

Genetics

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).

Clinical Sensitivity - Sequencing with CNV PGxome

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.

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

Testing Strategy

This test provides full coverage of all coding exons of the HPD gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing.

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 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.

Gene

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

Diseases

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

Citations

  • 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

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

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.

For Requisition Forms, visit our Forms page


Specimen Types

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