Autosomal Dominant Retinitis Pigmentosa 31 (RP31) via the TOPORS Gene

Retinitis pigmentosa (RP; OMIM # 609923) or rod cone dystrophies (RCDs), represent a group of hereditary retinal dystrophies with a worldwide prevalence of ~1 in 4000 (Booij et al. J Med Genet 42 (11): e67, 2005). RP is clinically characterized by retinal pigment deposits visible on fundus examination, nyctalopia (night blindness), followed by progressive degeneration of the photoreceptors, which eventually leads to blindness (van Soest et al. Surv Ophthalmol 43(4):321-334,1999; Chakarova et al. Am J Hum Genet 81(5):1098-1103, 2007). RP31 affected patients have a unique perivascular retinal pigment epithelium (RPE) atrophy phenotype in the early stages of the disease (Chakarova et al., 2007).

Nonsyndromic RP is remarkably heterogeneous both clinically and genetically and exhibits autosomal dominant (ad), autosomal recessive (ar) or X-linked (XL) inheritance. To date, over 50 loci have been linked to nonsyndromic RP and 18, 27 and 2 genes have been identified that are associated with adRP, arRP, and XLRP, respectively (RetNet). TOPORS (OMIM # 609507), which encodes topoisomerase I-binding arginine-serine rich protein, is one of the recently identified genes that is associated with RP and is responsible for 1-2% of adRP (Bowne et al. Mol Vis 14:922-927, 2008; Chakarova et al. Hum Mol Genet 20(5):975-987, 2011). Immunolocalization studies indicates that the TOPORS is localized to the basal body connecting cilium of the photoreceptor cells and may play a crucial role in regulating primary cilia-dependent photoreceptor development and function. (Chakarova et al., 2011).

There are about 10 mutations have been reported in TOPORS, which includes point mutations, small insertions and deletions (Human Gene Mutation Database). It has been reported that haploinsufficiency is a likely disease mechanism for TOPORS mutations. So far no copy number variants have been identified (Bowne et al., 2008). A recent study done by Selmer et al. (2010) identified a novel missense mutation, c.1205 A>C (p.Q402P), in TOPORS in all the affected members (19/19) in a large Norwegian family and this mutation showed complete co-segregation with the disease (Selmer et al. Acta Ophthalmol 88(3):323-328, 2010).

TOPORS mutation frequency analysis was done with a cohort of 215 adRP probands, where 89 of them did not have mutations in other known adRP genes. Only two of the 89 probands had TOPORS mutations (~1%), which was not found in 90 unrelated normal control samples. It is been reported that the addition of TOPORS to the list of adRP associated genes, mutations can be identified in 60% of the affected adRP patients (Bowne et al. Mol Vis 14:922-927, 2008).

So far, no gross deletions or duplications have been reported in TOPORS (The Human Gene Mutation Database).

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