Hereditary Hemochromatosis via the SLC40A1 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
11679 SLC40A1 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
11679SLC40A181479 81479(x2) $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

Clinical Features and Genetics

Clinical Features

Hereditary hemochromatosis (HH) is a disorder characterized by excess iron overload. In type 4 HH, iron overload is due to alterations in ferroportin, the iron transporting protein found on macrophages and on the basolateral surface of enterocytes. There are two different forms of type 4 HH: classical (45% cases) and non-classical (30%). In 25% of cases, distinguishing type 4 classical or non-classical forms is unclear (Mayr et al. 2010). In patients with classical type 4 HH, iron accumulation occurs in macrophages, mainly Kupffer cells in the liver whereas non-classical type 4 HH patients show hepatocyte iron deposition similar to patients with type 1 HH. Symptom onset is primarily after the third decade of life with patients initially presenting with fatigue and arthritis (typically in metacarpophalangeal joints). Chronic iron deposition can result in advanced fibrotic liver disease, cirrhosis, hepatocellular carcinoma, atherosclerosis, arthritis, fatigue, diabetes, hypogonadism, cardiomyopathy, and diffuse skin pigmentation (Mayr et al. 2010).

There are six types of hemochromatosis each due to a different genetic cause: type 1- HFE, type 2- HAMP or HFE2/HJV, type 3- TFR2, type 4- SLC40A1, type 5- FTH1, and type 6- FTL. Type 1 hemochromatosis is the most prevalent form of the disease and represents >90% of cases (Vujic 2014). Genetic testing can be helpful in differential diagnosis of HH from other liver function disorders and for determining the underlying cause of hemochromatosis (Zarrilli et al. 2013). Phlebotomy is standard treatment to reduce serum iron levels and prevent progressive liver damage.

Genetics

Hemochromatosis is inherited in an autosomal recessive mode through pathogenic variants in the HFE, HAMP, HFE2/HJV, or TRF2 genes or an autosomal dominant pattern through pathogenic variants in the SLC40A1, FTH1, or FTL genes (Santos et al. 2012; Njajou et al. 2001). The SLC40A1 gene encodes ferroportin, an iron transporting protein that is negatively regulated by hepcidin. To date, missense variants account for >90% of the causative variants and nonsense, gross deletions and frameshift variants have not been reported in the SLC40A1 gene (Détivaud et al. 2013; Callebaut et al. 2014). An in-frame deletion and splice site alteration have been reported in two individuals (Wallace et al. 2002; Lee et al. 2007). In classical type 4 HH patients, loss of function variants lead to loss of ferroportin expression and intracellular retention of iron within cells, primarily macrophages. Non-classic type 4 HH patients have gain of function variants disrupting interactions with the negative regulator hepcidin. Penetrance for type 4 HH is variable and influenced by both environmental factors and HFE pathogenic variants (Le Lan et al. 2011).

Clinical Sensitivity - Sequencing with CNV PGxome

Analytical sensitivity for detection of variants in the SLC40A1 gene is > 99%. In hyperferritinemia patients where types 1-3 and 6 HH were ruled out, pathogenic variants in the SLC40A1 gene were found in all 44 patients (Callebaut et al 2014).

Testing Strategy

This test provides full coverage of all coding exons of the SLC40A1 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

Patients with classical type 4 HH present with hyperferritinemia, low to normal transferrin saturation, and iron accumulation primarily in macrophages. Non-classical type 4 patients present with elevated transferrin saturation (>45%), hyperferritinemia, and iron overload primarily in hepatocytes. Secondary symptoms related to iron overload may include liver cirrhosis, diabetes mellitus and arthropathy (Détivaud et al. 2013; Callebaut et al. 2014).

Gene

Official Gene Symbol OMIM ID
SLC40A1 604653
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Hemochromatosis Type 4 AD 606069

Citations

  • Callebaut I. et al. 2014. Human Molecular Genetics. 23: 4479-90. PubMed ID: 24714983
  • D├ętivaud L. et al. 2013. Human Mutation. 34: 1529-36. PubMed ID: 23943237
  • Le Lan C. et al. 2011. Gastroenterology. 140: 1199-1207.e1-2. PubMed ID: 21199650
  • Lee P.L. et al. 2007. Acta Haematologica. 118: 237-41. PubMed ID: 18160816
  • Mayr R. et al. 2010. Journal of Hepatology. 53: 941-9. PubMed ID: 20691492
  • Njajou O.T. et al. 2001. Nature Genetics. 28: 213-4. PubMed ID: 11431687
  • Santos P.C. et al. 2012. International Journal of Molecular Sciences. 13: 1497-511. PubMed ID: 22408404
  • Vujic M. 2014. Frontiers in Pharmacology. 5: 42. PubMed ID: 24653703
  • Wallace D.F. et al. 2002. Blood. 100: 692-4. PubMed ID: 12091366
  • Zarrilli F. et al. 2013. Biomed Research International. 2013: 1-7. PubMed ID: 24222913

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.
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