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Iron-Refractory Iron Deficiency Anemia (IRIDA) via the TMPRSS6 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
8027 TMPRSS6 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8027TMPRSS681479 81479,81479 $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.

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

Iron-refractory Iron deficiency anemia (IRIDA) is a disorder of impaired iron metabolism resulting in anemia due to a shortage of iron required for hemoglobin production. In 2008, the molecular mechanism of IRIDA was identified, with pathogenic variants in the TMPRSS6 gene being the primary cause of disease (Finberg et al. 2008). A hallmark of IRIDA is little to no improvement of anemia with oral iron treatment (Donker et al. 2014). The degree of anemia is variable, but primarily mild and most pronounced during childhood. Other symptoms include fatigue, weakness, pale skin, dizziness, and exercise-induced dyspnea. Genetic testing is helpful in differential diagnosis of IRIDA from nutritional iron deficiency and other acquired forms of microcytic anemia including H. pylori infection, gastro-intestinal malabsorption, and bleeding (De Falco et al. 2013).

Genetics

IRIDA is inherited in an autosomal recessive manner through pathogenic variants in the TMPRSS6 gene. Over 70 causative variants have been identified throughout the TMPRSS6 gene to date with over half being missense variants that lead to impaired enzymatic activity (De Falco et al. 2010). Nonsense, small insertions/deletions, and splice site alterations have also been reported (De Falco et al. 2010; De Falco et al. 2013). Gross deletions have only been seen in one patient that was compound heterozygous for a second missense variant (Tchou et al. 2009). The TMPRSS6 gene encodes the protein MT-2, which is a transmembrane serine protease which down regulates hepicidin, the master regulator of iron homeostasis. Hepcidin prevents basolateral transport of iron in gut enterocytes and release of iron from macrophages through inhibition of the iron exporter ferroportin (De Falco et al. 2013). Additionally, Tmprss6 knockout mice exhibit iron deficiency anemia due to unsuppressed hepcidin expression and mimic IRIDA syndrome (Folgueras et al. 2008).

Clinical Sensitivity - Sequencing with CNV PGxome

Analytical sensitivity should be high as a gross deletion in the TMPRSS6 gene has only been reported once (Tchou et al. 2009; De Falco et al. 2014; De Falco et al. 2013). All other variants should be detectable by sequencing. Clinical sensitivity cannot be estimated because only a small number of patients have been reported.

Testing Strategy

This test provides full coverage of all coding exons of the TMPRSS6 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

Laboratory findings indicative of IRIDA include decreased Hb (6-10.5 g/dL), MCV (46-68 fL), MCH (12-20 pg), transferrin saturation (3-9%), and elevated soluble transferring receptor (6-25 mg/L) and serum hepcidin levels (5-18 nM). Other indicators for IRIDA are unresponsiveness to oral iron with partial recovery after parenteral iron administration and microcytic hypochromic anemia. Serum ferritin levels are usually within normal range (De Falco et al. 2010). This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in TMPRSS6.

Gene

Official Gene Symbol OMIM ID
TMPRSS6 609862
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Microcytic Anemia AR 206200

Citations

  • De Falco L, Sanchez M, Silvestri L, Kannengiesser C, Muckenthaler MU, Iolascon A, Gouya L, Camaschella C, Beaumont C. 2013. Iron refractory iron deficiency anemia. Haematologica 98: 845–853. PubMed ID: 23729726
  • De Falco L, Silvestri L, Kannengiesser C, Morán E, Oudin C, Rausa M, Bruno M, Aranda J, Argiles B, Yenicesu I, Falcon-Rodriguez M, Yilmaz-Keskin E, Kocak U, Beaumont C, Camaschella C, Iolascon A, Grandchamp B, Sanchez M. 2014. Functional and Clinical Impact of Novel Tmprss6 Variants in Iron-Refractory Iron-Deficiency Anemia Patients and Genotype-Phenotype Studies. Human Mutation 35:1321-1329. PubMed ID: 25156943
  • De Falco L, Totaro F, Nai A, Pagani A, Girelli D, Silvestri L, Piscopo C, Campostrini N, Dufour C, Manjomi FA, Minkov M, Vuurden DG Van, Feliu A, Kattamis A, Camaschella C, Iolascon A. 2010. Novel TMPRSS6 mutations associated with iron-refractory iron deficiency anemia (IRIDA). Human Mutation 31: E1390–E1405. PubMed ID: 20232450
  • Donker AE, Raymakers RAP, Vlasveld LT, Barneveld T van, Terink R, Dors N, Brons PPT, Knoers NVAM, Swinkels DW. 2014. Practice guidelines for the diagnosis and management of microcytic anemias due to genetic disorders of iron metabolism or heme synthesis. Blood 123: 3873–3886; quiz 4005. PubMed ID: 24665134
  • Finberg KE, Heeney MM, Campagna DR, Aydinok Y, Pearson HA, Hartman KR, Mayo MM, Samuel SM, Strouse JJ, Markianos K, Andrews NC, Fleming MD. 2008. Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA). Nature Genetics 40: 569–571. PubMed ID: 18408718
  • Folgueras AR, Lara FM de, Pendás AM, Garabaya C, Rodríguez F, Astudillo A, Bernal T, Cabanillas R, López-Otín C, Velasco G. 2008. Membrane-bound serine protease matriptase-2 (Tmprss6) is an essential regulator of iron homeostasis. Blood 112: 2539–2545. PubMed ID: 18523150
  • Tchou I, Diepold M, Pilotto P-A, Swinkels D, Neerman-Arbez M, Beris P. 2009. Haematologic data, iron parameters and molecular findings in two new cases of iron-refractory iron deficiency anaemia. Eur. J. Haematol. 83: 595–602. PubMed ID: 19708871

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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