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Familial Exudative Vitreoretinopathy 5 (FEVR5) via the TSPAN12 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
8549 TSPAN12 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8549TSPAN1281479 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

  • Dana Talsness, PhD

Clinical Features and Genetics

Clinical Features

Familial exudative vitreoretinopathy (FEVR) is an inherited ocular disorder characterized by abnormal vascularisation of the peripheral retina. FEVR penetrance is reported to be close to 100%, but shows a variable clinical expression, even within families. At the milder end of the disease spectrum, individuals are asymptomatic or may have a small area of avascularity in the peripheral retina, whereas at the severe end, individuals are legally blind during the first decade of life (Toomes et al. 2004). The secondary retinal pathologies include retinal folds and detachment in association with retinal traction, subretinal or intraretinal exudation, and fibrovascular proliferation at the junction between vascularised and non-vascularised retina. Rarely retinoschisis and giant retinal tears have been reported (Toomes and Downey 2011).

Genetics

FEVR has been linked to five different loci (EVR1 to EVR5). EVR1, EVR3 and EVR4 are located on 11q13–23; EVR2 is on X-chromosome and EVR5 is on chromosome 7. The EVR4 locus has been reported as extremely rich in genes that are associated with a range of retinal disorders like Best disease (BEST1), oculocutaneous albinism (TYR), retinitis pigmentosa (ROM1), Usher’s syndrome (MYO7A), Bardet Biedel syndrome (BBS1) and inflammatory vitreoretinopathy (CAPN5) (Bamashmus et al. 2000; Toomes et al. 2004b). FEVR is genetically heterogeneous and exhibits autosomal dominant (ad), autosomal recessive (ar) and X-linked inheritance (XL) with ad being the most common mode. So far four causative genes, LRP5 (low-density lipoprotein 5), FZD4 (frizzled 4), NDP (norrin), and TSPAN12 (tetraspanin-12,) have been identified. The proteins encoded by these genes act as ligand and receptors in Wnt signaling pathway, which is highly conserved among species and plays an important role in eye organogenesis and angiogenesis (Warden et al. 2007; Nikopoulos et al. 2010). Together, all four genes are responsible for only 50% of the FEVR cases, indicating the significant genetic heterogeneity of FEVR, and that additional FEVR genes involved in Wnt signaling pathway remain to be identified (Poulter et al. 2010).

TSPAN12, which is located on chromosome 7, encodes the protein tetraspanin that belongs to the 33 member four-transmembrane-domain protein superfamily (also referred to as tetraspans or TM4SF proteins). These proteins have the ability to interact with each other and also with other proteins to form large multimolecular membrane complexes called tetraspanin webs (Poulter et al. 2010; Hemler 2005). These transmembrane proteins have been implicated in a diverse range of biological processes, including signal transduction, metastasis, cell proliferation, differentiation and migration (Poulter et al. 2010; Berditchevski 2001; Yunta and Lazo 2003; Levy and Shoham 2005). TSPAN12 expression is shown to be restricted to the retinal vasculature and is required for retinal vascular development. TSPAN12 enhances Norrin/β-Catenin Signaling in retinal endothelial cells (Junge et al. 2009). TSPAN12 mutations are associated with both adFEVR and arFEVR. However, mutations in both alleles of TSPAN12 have been reported to cause severe form of FEVR or retinal dysplasia (Poulter et al. 2012). About 20 mutations in TSPAN12 have been reported to cause FEVR and include missense, nonsense, splicing, small deletions, a small insertion and one gross deletion (Human Gene Mutation Database).

Clinical Sensitivity - Sequencing with CNV PGxome

Mutations in the TSPAN12 gene account for 3-10% of familial exudative vitreoretinopathy cases (Poulter et al. 2010; Toomes and Downey 2011).

Testing Strategy

This test provides full coverage of all coding exons of the TSPAN12 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

All patients with symptoms suggestive of familial exudative vitreoretinopathy (FEVR), and relatives of patients with known TSPAN12 mutations.

Gene

Official Gene Symbol OMIM ID
TSPAN12 613138
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Exudative Vitreoretinopathy 5 AD 613310

Citations

  • Bamashmus MA, Downey LM, Inglehearn CF, Gupta SR, Mansfield DC. 2000. Genetic heterogeneity in familial exudative vitreoretinopathy; exclusion of the EVR1 locus on chromosome 11q in a large autosomal dominant pedigree. Br J Ophthalmol 84: 358–363. PubMed ID: 10729291
  • Berditchevski F. 2001. Complexes of tetraspanins with integrins: more than meets the eye. Journal of Cell Science 114: 4143–4151. PubMed ID: 11739647
  • Hemler ME. 2005. Tetraspanin functions and associated microdomains. Nat. Rev. Mol. Cell Biol. 6: 801–811. PubMed ID: 16314869
  • Human Gene Mutation Database (Bio-base).
  • Junge HJ, Yang S, Burton JB, Paes K, Shu X, French DM, Costa M, Rice DS, Ye W. 2009. TSPAN12 Regulates Retinal Vascular Development by Promoting Norrin- but Not Wnt-Induced FZD4/β-Catenin Signaling. Cell 139: 299–311. PubMed ID: 19837033
  • Levy S, Shoham T. 2005. Protein-protein interactions in the tetraspanin web. Physiology (Bethesda) 20: 218–224. PubMed ID: 16024509
  • Nikopoulos K. et al. 2010. Human Mutation. 31: 656-66. PubMed ID: 20340138
  • Poulter J.A. et al. 2010. American Journal of Human Genetics. 86: 248-53.  PubMed ID: 20159112
  • Poulter JA, Davidson AE, Ali M, Gilmour DF, Parry DA, Mintz-Hittner HA, Carr IM, Bottomley HM, Long VW, Downey LM, Sergouniotis PI, Wright GA, et al. 2012. Recessive Mutations in TSPAN12 Cause Retinal Dysplasia and Severe Familial Exudative Vitreoretinopathy (FEVR). Investigative Ophthalmology & Visual Science 53: 2873–2879. PubMed ID: 22427576
  • Toomes C, Downey L. 2011. Familial Exudative Vitreoretinopathy, Autosomal Dominant. 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: 20301326
  • Toomes C, Downey LM, Bottomley HM, Scott S, Woodruff G, Trembath RC, Inglehearn CF. 2004. Identification of a fourth locus (EVR4) for familial exudative vitreoretinopathy (FEVR). Mol. Vis. 10: 37–42. PubMed ID: 14737064
  • Toomes C. et al. 2004. American Journal of Human Genetics. 74: 721-30. PubMed ID: 15024691
  • Warden S.M. et al. 2007. Seminars in Ophthalmology. 22: 211-7.  PubMed ID: 18097984
  • Yunta M, Lazo PA. 2003. Tetraspanin proteins as organisers of membrane microdomains and signalling complexes. Cell. Signal. 15: 559–564. PubMed ID: 12681443

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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