Comprehensive Vitreoretinopathy Panel

Vitreoretinopathy or Familial Exudative Vitreoretinopathy (FEVR) is an inherited rare ocular disorder characterized by abnormal vascularisation of the peripheral retina. FEVR penetrance is reported to be high, but 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. PubMed ID: 15024691). 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 et al. 2011. PubMed ID: 20301326).

With the advent of gene therapy and other types of treatments, the identification of causative genes and variants is becoming increasingly important.

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FEVR Clinical trials

FEVR is genetically heterogeneous and exhibits autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL) inheritance with AD being the most common mode. Variants in LRP5 cause AR/AD FEVR (EVR4) and variants in NDP cause XL-FEVR (EVR2). Variants in TSPAN12 and FZD4 cause AD FEVR (EVR1 and EVR5 respectively). Together, these four genes are responsible for about 50% of FEVR cases (Poulter et al. 2010. PubMed ID: 20159112).

KIF11 (Hu et al. 2016. PubMed ID: 26472404), COL2A1 (Richards et al. 2002. PubMed ID: 12205109), ZNF408 (Collin et al. 2013. PubMed ID: 23716654), CAPN5 (Rowell et al. 2012. PubMed ID: 23271883) and VCAN (Mukhopadhyay et al. 2006. PubMed ID: 16877430) have also been reported to be associated with AD Vitreoretinopathy.

LRP5 (low-density lipoprotein 5), FZD4 (frizzled 4), NDP (norrin), and TSPAN12 (tetraspanin-12) encoded proteins act as ligand and receptors in the Wnt signaling pathway, suggesting a critical role for this pathway in eye organogenesis and angiogenesis (Warden et al. 2007. PubMed ID: 18097984; Nikopoulos et al. 2010. PubMed ID: 20340138; Gilmour. 2015. PubMed ID: 25323851). Perturbations in the Wnt signaling pathway due to pathogenic variants in LRP5, FZD4 and NDP have also been linked to several other degenerative diseases. For instance, pathogenic variants in LRP5 cause AR osteoporosis-pseudoglioma syndrome, AD Osteosclerosis type1 and AD bone mineral density variability 1. Pathogenic variants in NDP cause a severe phenotype called Norrie disease and Coats disease. Pathogenic variants in FZD4 cause Retinopathy of prematurity (ROP). It has been shown that pathogenic variants in FZD4, LRP5 and NDP account for a small percentage of (3-12%) of ROP cases (Shastry. 2010. PubMed ID: 20738858; Shastry et al. 1997. PubMed ID: 9152134; Hiraoka et al. 2010. PubMed ID: 21151595), which explains the phenotypic similarities in FEVR and ROP and also suggests that the Wnt pathway is defective in both disorders.

Missense, splicing, small deletions/insertions, and gross deletions have been reported in these genes (listed in the below table) associated with Vitreoretinopathies (Human Gene Mutation Database). Narumi et al. reported gross deletions in LRP5 (Narumi et al. 2010. PubMed ID: 20034086). One gross deletion in TSPAN12 and none in FZD4 have been reported (Human Gene Mutation Database). A complete COL2A1 gene deletion has also been reported (Richards et al. 2010. PubMed ID: 20513134).

The three most frequently reported pathogenic variants are NDP c. 362G >A (p. Arg121Gln), FZD4 c. 313A >G (p.Met105Val), and c.1282_1285delGACA (p. Asp428Serfs*2) (Xiao et al. 2019. PubMed ID: 31827910).

See individual gene summaries for more information about molecular biology of gene products and spectra of pathogenic variants.

A mutation analysis in 20 affected families identified FZD4 pathogenic variants in 8 families (40%), LRP5 pathogenic variants in 2 families (10%), and NDP pathogenic variants in 2 families (10%) (Boonstra et al. 2009. PubMed ID: 19324841). In another study, Toomes et al. reported that together LRP5 (15%) and FZD4 (20%) account for 35% of FEVR cases (Toomes et al. 2004. PubMed ID: 15024691), whereas Nallathambi et al. reported that pathogenic variants in FZD4 were seen in 5.6% of the clinically diagnosed FEVR Indian patients (Nallathambi et al. 2006. PubMed ID: 17093393). Poulter et al. reported that the TSPAN12 gene alone accounted for 10% of FEVR cases (Poulter et al. 2010. PubMed ID: 20159112). According to Riveiro-Alvarez et al., ~85% of the patients clinically diagnosed with Norrie Disease have pathogenic sequence variants in NDP and the rest of the 15% had intragenic and submicroscopic deletions involving NDP and adjacent regions (Riveiro-Alvarez et al. 2005. PubMed ID: 16163268).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel typically provides 99.9% coverage of all coding exons of the genes 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 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).