Porphyria Cutanea Tarda Type II/Hepatoerythropoietic Porphyria via the UROD 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
8589 UROD 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8589UROD81479 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

Porphyria Cutanea Tarda (PCT) type II is metabolic disorder due to impairment of the fifth enzyme, uroporphyrinogen decarboxylase (UROD), in the heme biosynthetic pathway and is the most common form of porphyria affecting about 5-10 in 100,000 individuals. It is characterized by cutaneous photosensitivity resulting in blistering. Patients may also exhibit skin friability after minor trauma, facial hypertrichosis, hyperpigmentation, and pseudoscleroderma. Individuals with PCT type II have an increased risk for hepatocellular carcinoma. Symptom onset is typically in the fourth or fifth decade of life and is more common in men. There are three clinically indistinguishable types of PCT: type 1-sporadic, type II- familial with presence of UROD mutation, and type III- familial without presence of UROD mutation. PCT type II has relatively low penetrance with susceptibility being influenced by several factors including presence of HFE mutations, alcohol consumption, hepatitis C or HIV infection, smoking, or oral estrogen use (Sampietro et al. 1999). Genetic testing is helpful in confirming diagnosis of PCT subtypes and from other porphyria related disorders. Standard treatments typically involve monitoring of urinary porphyrin levels and phlebotomies to reduce iron stores. Avoidance of susceptibility factors and increased surveillance for hepatocellular carcinoma are also common for patients with PCT (Liu et al. 2013).

Hepatoerythropoietic porphyria (HEP) is the autosomal recessive form of PCT type II with affected individuals having biallelic mutations in the UROD gene. Clinical symptoms mirror congenital erythropoietic porphyria with skin blistering occurring in areas of sun exposure. Symptom onset primarily occurs in infancy and may include increased hair growth on sun exposed skin, reddish colored urine, and brownish colored teeth. Fewer than 100 cases have been reported to date with males and females being equally affected. Similar susceptibility factors for PCT type II also may exacerbate symptoms in HEP (Liu et al. 2013).

Genetics

PCT type II and HEP are inherited in autosomal dominant and recessive manners respectively through mutations in the UROD gene. PCT type II is a low penetrant disorder with clinical presentation of the disease being influenced by several susceptibility factors (Liu et al. 2013). Missense variants affecting UROD transcript stability are the most frequently identified causative variant and are found throughout the coding region (Phillips et al. 2001). Although less common, splicing alterations, small insertions/deletions, and nonsense variants have also been found in patients with PCT type II (Aarsand et al. 2009). In HEP, typically patients have a null and missense mutation in the UROD gene. Homozygosity for null alleles is lethal (Phillips et al. 2007). Mutations in the HFE gene have been shown to enhance disease severity (Mendez et al. 1998; Aarsand et al. 2009).

The UROD gene encodes the uroporhyrinogen decarboxylase enzyme which catalyzes the conversion of uroporphyrinogen II to coproporphyringen III in the heme metabolic pathway. In tissues with impaired UROD activity, primarily blood and liver, oxidized porphyrins accumulate and are released into the plasma and deposited in the skin. When protoporphyrin accumulates in tissues it becomes photo-activated resulting in excess energy to be transferred to oxygen. This leads to heightened reactive oxygen species causing cellular damage and disease (Phillip et al. 2007).

Clinical Sensitivity - Sequencing with CNV PGxome

In a patient cohort containing both sporadic and familial PCT, mutations in the UROD gene were identified in 131 of 248 patients (Aarsand et al. 2009). Analytical sensitivity is >95% as large deletions cannot be detected by this method and have been reported in a few cases (Mendez et al. 1998; Liu et al. 2013).

Testing Strategy

This test provides full coverage of all coding exons of the UROD 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

Candidates for this test are patients displaying painful photosensitivity with skin blistering, the hallmark characteristics of PCT and HEP. Plasma fluorescence peaks at 634nm confirm presence of high free protoporphrin levels. Ideal candidates have known biochemical findings of elevated porphyrins in the urine and impaired hepatic UROD enzymatic activity (Aarsand et al. 2009; Liu et al. 2013). This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in UROD.

Gene

Official Gene Symbol OMIM ID
UROD 613521
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Familial Porphyria Cutanea Tarda AR, AD 176100

Citations

  • Aarsand AK, Boman H, Sandberg S. 2009. Familial and Sporadic Porphyria Cutanea Tarda: Characterization and Diagnostic Strategies. Clinical Chemistry 55: 795–803. PubMed ID: 19233912
  • Liu LU, Phillips J, Bonkovsky H. 2013. Hepatoerythropoietic Porphyria. In: Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(®), Seattle (WA): University of Washington, Seattle. PubMed ID: 24175354
  • Liu LU, Phillips J, Bonkovsky H. 2013. Porphyria Cutanea Tarda, Type II. In: Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(®), Seattle (WA): University of Washington, Seattle. PubMed ID: 23741761
  • Mendez M, Sorkin L, Rossetti MV, Astrin KH, C Batlle AM del, Parera VE, Aizencang G, Desnick RJ. 1998. Familial porphyria cutanea tarda: characterization of seven novel uroporphyrinogen decarboxylase mutations and frequency of common hemochromatosis alleles. Am. J. Hum. Genet. 63: 1363–1375. PubMed ID: 9792863
  • Phillips JD, Bergonia HA, Reilly CA, Franklin MR, Kushner JP. 2007. A porphomethene inhibitor of uroporphyrinogen decarboxylase causes porphyria cutanea tarda. Proceedings of the National Academy of Sciences 104: 5079–5084. PubMed ID: 17360334
  • Phillips JD. 2001. Functional consequences of naturally occurring mutations in human uroporphyrinogen decarboxylase. Blood 98: 3179–3185. PubMed ID: 11719352
  • Sampietro M, Fiorelli G, Fargion S. 1999. Iron overload in porphyria cutanea tarda. Haematologica 84: 248–253. PubMed ID: 10189391

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

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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


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