Familial Exudative Vitreoretinopathy 1 (FEVR1) via the FZD4 Gene

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; Ober et al. 1980). 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).

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. 2004; Toomes and Downey 2011). 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).

FZD4 encoded protein Frizzled 4 is a ligand receptor containing seven transmembrane domains and a cysteine-rich domain (CRD). FZD4 is widely expressed in neurons, endothelial cells, and mural cells of the retinal vasculature (Ye et al. 2009). FZD4 binds to Wnt ligands and activates the Wnt/β-catenin signaling pathway in conjunction with the coreceptors LRP5 and LRP6 (Logan and Nusse 2004; Masckauchán and Kitajewski 2006). NDP encoded Norrin is reported to be a highly specific ligand for FZD4 (Ye et al. 2009: Paes et al. 2011). Together, all the four genes (FZD4, LRP5, NDP and TSPAN12) are responsible for only 50% of the FEVR cases, indicating the significant genetic heterogeneity of FEVR and that additional FEVR genes remain to be identified (Poulter et al. 2010).

So far, about 60 pathogenic variants, mostly missense and nonsense, in FZD4 have been reported to be causative for autosomal dominant FEVR. No gross deletions have been reported in this gene (Human Gene Mutation Database).

Toomes et al. (2004) reported that together, FZD4 and LRP5 mutations account for 35% of FEVR cases in their familial exudative vitreoretinopathy (FEVR) patient cohort (15% LRP5 and 20% FZD4), (Toomes et al. 2004). A molecular study done in 20 families diagnosed with FEVR identified FZD4 mutations in 8 families (40%), (Boonstra et al. 2009).

This test provides full coverage of all coding exons of the FZD4 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).