NDP-Related Vitreoretinopathies via the NDP Gene

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).

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).

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).