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NDP-Related Vitreoretinopathies via the NDP 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
NDP 81404 81404,81403 $990
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
9209NDP81404 81404,81403 $990 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 platform).

Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing platform).

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

Turnaround Time

3 weeks on average for standard orders or 2 weeks 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.


Genetic Counselors


  • Dana Talsness, PhD

Clinical Features and Genetics

Clinical Features

NDP-related vitreoretinopathies are characterized by a spectrum of retinal pathology that occurs at birth and has varying degrees of severity.

The most severe form is Norrie Disease (ND), which is a rare disorder characterized by congenital blindness due to severe retinal dysgenesis. One third of ND affected individuals develop hearing loss and about one half exhibit intellectual disability (Ott et al. 2000). In some ND cases, more complex phenotypes such as microphthalmia, growth failure, and seizures are present. The other less severe phenotypes of NDP-related vitreoretinopathies include familial exudative vitreoretinopathy (FEVR), Coats disease, retinopathy of prematurity (ROP) and persistent hyperplastic primary vitreous (PHPV) (Sims 2009).

FEVR is characterized by abnormal vascularisation of the peripheral retina. FEVR penetrance is reported to be 100% and shows an extremely variable clinical expression, even within a family and is clearly asymmetric. 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).

Coats' disease is characterized by abnormal development of the retinal vessels (telangiectasis) which leads to the massive intraretinal and subretinal lipid deposition that in turn results in exudative retinal detachment. The classic form of Coats' disease is always isolated, unilateral and affects males. Often, it is difficult to differentiate advanced Coats' disease from retinoblastoma on ophthalmoscopic findings alone (Haik 1991).

Retinopathy of prematurity (ROP) is a multifactorial disease, which is characterized by complication of low gestational age and low birth weight. Early detection is very important in order to identify the independent risk factors for the development of ROP, which may lead to blindness (Delport et al. 2002; Mathew et al. 2002).

PHPV, also known as persistent fetal vasculature, is a rare congenital developmental malformation of the eye with an estimated prevalence ranging from approximately one in 2000 to one in 9000 patients. Bilaterality occurs in 9–17% of these cases. PHPV is characterized by a fibrovascular stalk that extends from the optic disc to the lens (Makino et al. 2013; Sims 1993; Shastry 2009).


All NDP-related vitreo-retinopathies are associated with mutations in the NDP gene, which is located on chromosome Xp11.4 and exhibits X-linked mode of inheritance. Approximately 95% of affected males have disease causing sequence variations in NDP (Sims 2009). Female carriers are often asymptomatic, but in rare cases may have some disease phenotype due to nonrandom X inactivation (Sims et al. 1997). So far, about 150 pathogenic sequence variations (including missense, nonsense, splicing,regulatory, small and gross insertions and deletions) in NDP have been associated with NDP-related vitreoretinopathies (Human Gene Mutation Database).

NDP encoded protein Norrin is a member of the cystine knot growth factor family and is a major regulator in the formation of the retinal vasculature during eye development (Ohlmann and Tamm 2012). It also protects retinal ganglion cells from oxygen-induced retinal vascular damage. Norrin is a retinal signaling molecule and is constitutively expressed in Müller cells of the eye. It specifically binds to Frizzled-4 (FZD4) receptors and activates the classic Wnt/β-catenin signaling pathway, which in turn induces neuroprotective effects of Norrin (Seitz et al. 2010; Braunger et al. 2013). Perturbations in the Wnt pathway have been associated with several retinal disorders (Lad et al. 2009).

Clinical Sensitivity - Sequencing with CNV PGxome

According to Riveiro-Alvarez et al., ~ 85% of the patients clinically diagnosed with Norrie Disease have point mutations in NDP gene (Riveiro-Alvarez et al. 2005). A molecular analysis in a four generation FEVR family revealed a missense mutation c.370C>T (Leu124Phe) in the highly conserved region of the NDP gene. It was detected in all of the affected males, but not in the unaffected family members or in normal controls (Chen et al. 1993).

Testing Strategy

This test provides full coverage of all coding exons of the NDP 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).

This test also covers the five noncoding NDP variants (c.-208+1G>A; c.-208+2T>G; c.-208+5G>A; c.-207-1G>A; c.*715T>C) that have been reported to be pathogenic (Human Gene Mutation Database).

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 NDP-related vitreoretinopathies (described in the clinical features section), and relatives of patients with known NDP mutations.


Official Gene Symbol OMIM ID
NDP 300658
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


  • Braunger BM, Ohlmann A, Koch M, Tanimoto N, Volz C, Yang Y, Bösl MR, Cvekl A, Jägle H, Seeliger MW, Tamm ER. 2013. Constitutive overexpression of Norrin activates Wnt/?-catenin and endothelin-2 signaling to protect photoreceptors from light damage. Neurobiol. Dis. 50: 1–12. PubMed ID: 23009755
  • Chen ZY, Battinelli EM, Fielder A, Bundey S, Sims K, Breakefield XO, Craig IW. 1993. A mutation in the Norrie disease gene (NDP) associated with X-linked familial exudative vitreoretinopathy. Nat. Genet. 5: 180–183. PubMed ID: 8252044
  • Delport SD, Swanepoel JC, Odendaal PJL, Roux P. 2002. Incidence of retinopathy of prematurity in very-low-birth-weight infants born at Kalafong Hospital, Pretoria. S. Afr. Med. J. 92: 986–990. PubMed ID: 12561416
  • Haik BG. 1991. Advanced Coats’ disease. Trans Am Ophthalmol Soc 89: 371–476. PubMed ID: 1808814
  • Human Gene Mutation Database (Bio-base).
  • Lad EM, Cheshier SH, Kalani MYS. 2009. Wnt-signaling in retinal development and disease. Stem Cells Dev. 18: 7–16. PubMed ID: 18690791
  • Makino S, Ohkubo Y, Tampo H. 2013. Prepapillary Vascular Loop Associated with Persistent Hyperplastic Primary Vitreous. Case Reports in Ophthalmological Medicine 2013: 1–2. PubMed ID: 23762694
  • Mathew MRK, Fern AI, Hill R. 2002. Retinopathy of prematurity: are we screening too many babies? Eye (Lond) 16: 538–542. PubMed ID: 12194065
  • Ohlmann A, Tamm ER. 2012. Norrin: molecular and functional properties of an angiogenic and neuroprotective growth factor. Prog Retin Eye Res 31: 243–257. PubMed ID: 22387751
  • Ott S, Patel RJ, Appukuttan B, Wang X, Stout JT. 2000. A novel mutation in the Norrie disease gene. J AAPOS 4: 125–126. PubMed ID: 10773814
  • Riveiro-Alvarez R. et al. 2005. Molecular Vision. 11: 705-12.  PubMed ID: 16163268
  • Seitz R, Hackl S, Seibuchner T, Tamm ER, Ohlmann A. 2010. Norrin Mediates Neuroprotective Effects on Retinal Ganglion Cells via Activation of the Wnt/ -Catenin Signaling Pathway and the Induction of Neuroprotective Growth Factors in Muller Cells. Journal of Neuroscience 30: 5998–6010. PubMed ID: 20427659
  • Shastry BS. 2009. Persistent hyperplastic primary vitreous: congenital malformation of the eye. Clin. Experiment. Ophthalmol. 37: 884–890. PubMed ID: 20092598
  • Sims KB, Irvine AR, Good WV. 1997. Norrie disease in a family with a manifesting female carrier. Arch. Ophthalmol. 115: 517–519. PubMed ID: 9109762
  • Sims KB. 2009. NDP-Related Retinopathies. In: Pagon RA, Adam MP, Bird TD, Dolan CR, Fong C-T, and Stephens K, editors. GeneReviews™, Seattle (WA): University of Washington, Seattle. PubMed ID: 20301506
  • Toomes C. et al. 2004. American Journal of Human Genetics. 74: 721-30. PubMed ID: 15024691


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

If ordering a Duo or Trio test, the proband and all comparator samples are required to initiate testing. If we do not receive all required samples for the test ordered within 21 days, we will convert the order to the most effective testing strategy with the samples available. Prior authorization and/or billing in place may be impacted by a change in test code.

Specimen Types

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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