Familial Exudative Vitreoretinopathy 5 (FEVR5) via the TSPAN12 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). 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. 2004b). 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). 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).

TSPAN12, which is located on chromosome 7, encodes the protein tetraspanin that belongs to the 33 member four-transmembrane-domain protein superfamily (also referred to as tetraspans or TM4SF proteins). These proteins have the ability to interact with each other and also with other proteins to form large multimolecular membrane complexes called tetraspanin webs (Poulter et al. 2010; Hemler 2005). These transmembrane proteins have been implicated in a diverse range of biological processes, including signal transduction, metastasis, cell proliferation, differentiation and migration (Poulter et al. 2010; Berditchevski 2001; Yunta and Lazo 2003; Levy and Shoham 2005). TSPAN12 expression is shown to be restricted to the retinal vasculature and is required for retinal vascular development. TSPAN12 enhances Norrin/β-Catenin Signaling in retinal endothelial cells (Junge et al. 2009). TSPAN12 mutations are associated with both adFEVR and arFEVR. However, mutations in both alleles of TSPAN12 have been reported to cause severe form of FEVR or retinal dysplasia (Poulter et al. 2012). About 20 mutations in TSPAN12 have been reported to cause FEVR and include missense, nonsense, splicing, small deletions, a small insertion and one gross deletion (Human Gene Mutation Database).

Mutations in the TSPAN12 gene account for 3-10% of familial exudative vitreoretinopathy cases (Poulter et al. 2010; Toomes and Downey 2011).

This test provides full coverage of all coding exons of the TSPAN12 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).