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Hereditary Spherocytosis via the EPB42 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
11291 EPB42 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
11291EPB4281479 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

  • Luke Drury, PhD

Clinical Features and Genetics

Clinical Features

Hereditary Spherocytosis (HS), also known as Minkowski-Chauffard disease, affects one in 2,000 individuals. HS is a condition where red blood cells lose their typical biconcave disc shape and appear spherical. The spherical shape impairs membrane flexibility making it hard for red blood cells to transverse narrow capillaries, especially in the spleen. This impairment causes anemia due to chronic extravascular hemolysis, jaundice, formation of bilirubin gallstones, reticulocytosis and splenomegaly (Aster et al. 2013; An and Mohandas 2008). Disease severity can range with 20-30% having mild form, 60-70% having moderate form, and 10-20% having severe form of HS. People with mild forms may be asymptomatic whereas severe forms of the disease present in newborns with life threatening anemia and require blood transfusions. There are five types of HS defined by the gene mutation causative for disease: Type I-ANK1, type 2-SPTB, type 3-SPTA1, type 4-SLC4A1, and type 5-EPB42 (Bolton-Maggs et al. 2004; Delaunay 2007). Type 5 HS makes up less than 5% of cases and is predominantly found in Japanese.

Genetics

HS in inherited in an autosomal dominant manner in 75% of cases through mutations in the ANK1, SPTB, and SLC4A1 genes. Autosomal recessive forms are inherited through mutations in the ANK1, SPTA1, and EPB42 genes (Bolton-Maggs et al. 2004). Most mutations reported to date are private with de novo dominant mutations being six times more common than recessive mutations (Miraglia del Giudice et al. 2001). Mutations in the ANK1, SPTB, SLC4A1, SPTA1, and EPB42 genes account for 60%, 10%, 15%, 10%, and 5% cases of HS respectively (An and Mohandas 2008). HS type 5 is inherited through an autosomal recessive manner through mutations in the EPB42 gene. Causative mutations are predominantly missense leading to impaired protein stability and a loss of Protein 4.2. Splicing mutations and small deletions make up the minority of cases (An and Mohandas 2008; Bolton-Maggs et al. 2004). Gross deletions have not been reported to date. Alpha thalassemia through mutations in the HBA1 and HBA2 genes has been shown to coexist within patients with EPB42 mutations with both diseases contributing to anemia (Maciaq et al. 2009). The EPB42 gene encodes for Protein 4.2 which is an anchoring protein linking ankryin and specrin to the membrane. These interactions are critical for maintaining the hallmark biconcave disc morphology of red blood cells and providing elasticity to navigate narrow vasculature (An and Mohandas 2008).

Clinical Sensitivity - Sequencing with CNV PGxome

Mutations in the EPB42 gene are causative for <5% of HS. Analytical sensitivity should be high as all mutations reported to date are detected by NextGen sequencing (An and Mohandas 2008).

Testing Strategy

This test provides full coverage of all coding exons of the EPB42 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 this test are patients showing features consistent with HR (Spherocytes in peripheral blood smears, anemia and reticulocytosis) and a family history for the disorder. Other typical pathological features include increased MCHC, increased RDW, and heightened sensitivity via Osmotic fragility test. HS may be differentiated between autoimmune and alloimmune hemolytic anemia via a negative Coombs test (Aster et al. 2013). This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in EPB42.

Gene

Official Gene Symbol OMIM ID
EPB42 177070
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Spherocytosis, Type 5 612690

Citations

  • An X, Mohandas N. 2008. Disorders of red cell membrane. Br. J. Haematol. 141: 367–375. PubMed ID: 18341630
  • Aster, JC, Pozdnyakova, O, Kutok, JL. Hematopathology. Philadelphia: Elsevier Saunders, 2013.
  • Bolton-Maggs PHB, Langer JC, Iolascon A, Tittensor P, King M-J, General Haematology Task Force of the British Committee for Standards in Haematology. 2012. Guidelines for the diagnosis and management of hereditary spherocytosis--2011 update. Br. J. Haematol. 156: 37–49. PubMed ID: 22055020
  • Delaunay J. 2007. The molecular basis of hereditary red cell membrane disorders. Blood Rev. 21: 1–20. PubMed ID: 16730867
  • Maciag M, Adamowicz-Salach A, Siwicka A, Spychalska J, Burzynska B. 2009. The use of real-time PCR technique in the detection of novel protein 4.2 gene mutations that coexist with thalassaemia alpha in a single patient. Eur. J. Haematol. 83: 373–377. PubMed ID: 19508687
  • Miraglia del Giudice E, Nobili B, Francese M, D’Urso L, Iolascon A, Eber S, Perrotta S. 2001. Clinical and molecular evaluation of non-dominant hereditary spherocytosis. Br. J. Haematol. 112: 42–47. PubMed ID: 11167781

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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