TSPAN12 was first reported in relation to exudative vitreoretinopathy in 2010 (Nikopoulos et al., PMID: 20159111; Poulter et al., PMID: 20159112). TSPAN12-related exudative vitreoretinopathy is an inherited blinding disorder caused by defects in the development of retinal vasculature. There is extensive variation in disease severity among patients, even between members of the same family. TSPAN12 was further reported be associated with exudative vitreoretinopathy in a semidominant manner in 4 families in 2012 (Poulter et al., PMID: 22427576).
Seven variants (missense, nonsense, frameshift, and canonical splicing) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function.
This gene-disease association is also supported by animal models and TSPAN12 protein being a part of the Norrin-LRP5-FZD4 signaling complex.
In summary, TSPAN12 is definitively associated with autosomal dominant or more appropriately semidominant TSPAN12-related exudative vitreoretinopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the Retina GCEP on January 6th, 2022 (SOP Version 8).
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