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Variegate Porphyria via the PPOX 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
11601 PPOX 81406 81406,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
11601PPOX81406 81406(x1), 81479(x1) $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.

Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing backbone).

Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing backbone).

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 13 days on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn 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

  • Luke Drury, PhD

Clinical Features and Genetics

Clinical Features

Variegate Porphyria (VP) is a metabolic disorder due to impairment of the seventh enzyme, protoporphyrinogen oxidase (PPOX), in the heme biosynthesis pathway. VP prevalence is highest in South African populations with 3 in 1,000 individuals compared to Europeans where 1 in 100,000 are affected. Onset primarily occurs after puberty with patients presenting with cutaneous and/or neurovisceral symptoms. Cutaneous symptoms are most common with VP patients and mirror patients with porphyria cutanea tarda (PCT) and hereditary coproporphyria (HCP). Chronic blistering occurs at sun exposed skin areas and can lead to scarring, thickening, abnormal pigmentation, and milia (Whatley et al. 1999; Singal and Anderson 2013). Neurovisceral symptoms mimic patients with acute intermittent porphyria (AIP) and include acute attacks leading to abdominal pain, nausea, vomiting, tachycardia, and hypertension. Attacks may be provoked by certain drugs, stress, caloric restriction, or steroid hormones. VP penetrance is low with the majority of patients being asymptomatic throughout life. Biochemical analysis showing elevated porphobilinogen (PBG) and aminolevulinic acid (ALA) in urine are primary indicators for VP, but may appear normal during asymptomatic phases (Whatley et al. 1999; Singal and Anderson 2013). Genetic testing is often helpful for differential diagnosis of VP from other forms of porphyria and for establishing diagnosis during asymptomatic phases. Diagnosis of VP in asymptomatic individuals allows management of acute attacks through avoidance of symptomatic triggers mentioned above (Whatley et al. 2009).

Genetics

VP is inherited in an autosomal dominant manner through pathogenic variants in the PPOX gene. In rare cases, autosomal recessive forms have been reported with one mutated allele possessing some enzymatic activity. These patients presented with VP in childhood and intellectual disability (Frank et al. 1998). A founder mutation, c.175C>T (p.Arg59Trp), impairs PPOX enzymatic activity and is estimated to be present in 3 per 1,000 individuals in South African populations and account for 95% of these cases (Messnier et al. 1996). In a study of western European individuals with VP, missense (38%), small insertions/deletions (36%), splice site (14%), and nonsense (11%) changes were reported (Whatley et al. 1999). Gross deletions have been reported in rare cases and occur within exons 5 through 9 (Barbaro et al. 2013). Penetrance for VP is low with the majority of individuals heterozygous for a pathogenic variant in the PPOX gene being asymptomatic (Singal and Anderson 2013). The PPOX gene encodes the protoporphyrinogen oxidase enzyme which is involved in heme synthesis and catalyzes the oxidation of protoporphyrinogen to protoporphyrin. This enzymatic reaction is the seventh step in heme synthesis (Singal and Anderson 2013).

Clinical Sensitivity - Sequencing with CNV PGxome

In a series of 103 patients where VP diagnosis was established by elevated fecal porphyrin, decreased PPOX activity, and elevated plasma porphyrin fluorescence, pathogenic variants were identified in 96% of cases (Whatley et al. 1999). Analytical sensitivity is >95% for detection of pathogenic variants by this method (Singal and Anderson 2013).

Two gross deletions, encompassing exons 5-6 and 5-9, have been reported to date. The clinical sensitivity is difficult to estimate due to the limited number of cases, but appears to be relatively low.

Testing Strategy

This test provides full coverage of all coding exons of the PPOX 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. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).

Indications for Test

Candidates for VP testing have biochemical analyses indicating elevated ALA, PGB, and uroporphyrin in urine and increased plasma porphyrin fluorescence (626nm). Ideal candidates present with both neurovisceral attacks and cutaneous symptoms indicative of VP (Whatley et al. 1999; Singal and Anderson 2013).

Gene

Official Gene Symbol OMIM ID
PPOX 600923
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Variegate Porphyria AD 176200

Citations

  • Barbaro M. et al. 2013. Orphanet Journal of Rare Diseases. 8: 13. PubMed ID: 23324528
  • Frank J. et al. 1998. The Journal of Investigative Dermatology. 110: 452-5. PubMed ID: 9540991
  • Meissner P.N. et al. 1996. Nature Genetics. 13: 95-7. PubMed ID: 8673113
  • Singal A.K. and Anderson K.E.. 2013. Variegate Porphyria. 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: 23409300
  • Whatley S.D. et al. 1999. American Journal of Human Genetics. 65: 984-94. PubMed ID: 10486317
  • Whatley S.D. et al. 2009. Clinical Chemistry. 55: 1406-14. PubMed ID: 19460837

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.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

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

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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ORDER OPTIONS

View Ordering Instructions

1) Select Test Method (Backbone)


1) Select Test Type


2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

No Additional Test Options are available for this test.

Note: acceptable specimen types are whole blood and DNA from whole blood only.
Total Price: $
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