TOPORS was first reported in relation to autosomal dominant retinitis pigmentosa (adRP) in 2005 (by Papaioannou et al., PMID: 16189705). Retinitis pigmentosa is a progressive disease, with common symptoms of night blindness, tunnel vision and reduced visual acuity. It is a clinically and genetically heterogenous, with more than 250 genes reported to be involved in different RP modes of inheritance. Variants in the TOPORS gene are thought to cause defects in the structure of photoreceptor connecting cilium, leading to photoreceptor degeneration and RP. Curiously, although TOPORS is ubiquitously expressed, variants in TOPORS are only known to cause adRP.
Ten variants (three nonsense, five frameshift, and two missense) that have been reported in sixteen probands in eleven publications (PMIDs: 17924349, 28041643, 18509552, 24938718, 31736247, 28224992, 19183411, 19373681, 28453362, 33576794, 33691693) are included in this curation. Additionally, two families were scored in which TOPORS mutations were found to co-segregate with adRP for a combined LOD score of 8.81 (PMIDs: 18509552 and 19183411). 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 haploinsufficiency.
This gene-disease association is also supported by expression studies showing that TOPORS is expressed in retina tissue (PMIDs: 21159800, 28940711, 17924349). TOPORS also performs a similar biochemical function to the RPGR protein, which is definitively associated with X-linked retinitis pigmentosa. Finally, Chakarova et al. provide evidence for the pathogenicity of TOPORS mutations in a zebrafish model (PMID: 21159800).
In summary, TOPORS is definitively associated with TOPORS-related retinopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification has been approved by the ClinGen Retina GCEP on April 6, 2023 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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