Familial Exudative Vitreoretinopathy via the RCBTB1 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. 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).

FEVR has been linked to five different loci (EVR1 to EVR5). EVR1, EVR3 and EVR4 are located on 11q13–23; EVR2 is on the 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 primary 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, all 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 variants in RCBTB1 have been implicated in autosomal recessive isolated and syndromic Retinal Dystrophy (Coppieters et al. 2016. PubMed ID: 27486781), autosomal dominant Coats disease, and autosomal dominant familial exudative vitreoretinopathy (Wu et al. 2016. PubMed ID: 26908610). About 5 pathogenic variants RCBTB1 have been reported to be causative (Human Gene Mutation Database). Missense variants have reported in patients with retinal disorders. Of note, pathogenic variants that result in truncated proteins and lead to haploinsufficiency of RCBTB1 have been reported in patients with Coats disease and FEVR (Coppieters et al. 2016. PubMed ID: 27486781; Wu et al. 2016. PubMed ID: 26908610)

Due to the genetic heterogeneity and limited number of cases, predicting clinical sensitivity is challenging. Analytical sensitivity should be high because all pathogenic variants reported are detectable by sequencing.

This test provides full coverage of all coding exons of the RCBTB1 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).