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Familial Exudative Vitreoretinopathy and Retinitis Pigmentosa via the ZNF408 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
3959 ZNF408 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
3959ZNF40881479 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. PubMed ID: 14737064). 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. PubMed ID: 20301326).

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. PubMed ID: 10729291; Toomes et al. 2004. PubMed ID: 15024691). 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 the Wnt signaling pathway, which is highly conserved among species and plays an important role in eye organogenesis and angiogenesis (Warden et al. 2007. PubMed ID: 18097984). Together, these 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. PubMed ID: 20159112).

Pathogenic missense variants in ZNF408 have been documented causative for both autosomal dominant and autosomal recessive vitreoretinopathy (Collin et al. 2013. PubMed ID: 23716654; Avila-Fernandez et al. 2015. PubMed ID: 25882705). Of note, loss of function variants have been documented causative for autosomal recessive Retinitis pigmentosa (Avila-Fernandez et al. 2015. PubMed ID: 25882705; Bravo-Gil et al. 2017. PubMed ID: 28157192). About 10 pathogenic variants in ZNF408 have been reported to be causative to date (Human Gene Mutation Database). Missense, nonsense, splicing and small frameshift deletion variants have been documented (Human Gene Mutation Database).

Functional studies revealed that ZNF408 is crucial for the development of zebrafish retinal vasculature (Collin et al. 2013. PubMed ID: 23716654).

Clinical Sensitivity - Sequencing with CNV PGxome

A study indicated that ZNF408 accounted for 2.7 % of the familial exudative vitreoretinopathy cases (Musada et al. 2016. PubMed ID: 27316669).

Testing Strategy

This test provides full coverage of all coding exons of the ZNF408 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). This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in ZNF408.

Gene

Official Gene Symbol OMIM ID
ZNF408 616454
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Diseases

Name Inheritance OMIM ID
Exudative Vitreoretinopathy 6 AD 616468
Retinitis Pigmentosa 72 AR 616469

Citations

  • Avila-Fernandez et al. 2015. PubMed ID: 25882705
  • Bamashmus et al. 2000. PubMed ID: 10729291
  • Bravo-Gil et al. 2017. PubMed ID: 28157192
  • Collin et al. 2013. PubMed ID: 23716654
  • Human Gene Mutation Database (Biobase).
  • Musada et al. 2016. PubMed ID: 27316669
  • Poulter et al. 2010. PubMed ID: 20159112
  • Toomes and Downey 2011. PubMed ID: 20301326
  • Toomes et al. 2004. PubMed ID: 14737064
  • Toomes et al. 2004. PubMed ID: 15024691
  • Warden et al. 2007. PubMed ID: 18097984

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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