Retinitis Pigmentosa via the RP1 Gene

Retinitis pigmentosa (RP) or rod cone dystrophies (RCDs) represent a group of hereditary retinal dystrophies with a worldwide prevalence of ~1 in 4000 (Booij et al. 2005). RP is clinically characterized by retinal pigment deposits visible on fundus examination, nyctalopia, followed by progressive degeneration of the photoreceptors, which eventually leads to blindness (van Soest et al. 1999).

Nonsyndromic and syndromic RP is remarkably heterogeneous both clinically and genetically. RP exhibits autosomal dominant (ad, 15%-25% of the cases), autosomal recessive (ar, 5%-20% of the cases) or X-linked (XL, 5%-15% of the cases) inheritance (Fahim et al. 2013). Unknown, simplex cases (single occurrence in a family) account for 40%-50%of cases and digenic inheritance has been reported (Fahim et al. 2013). To date, over 60 genes have been linked to nonsyndromic (~56 genes) and syndromic RP (RetNet; Daiger et al. 2013). It has been reported that it is now possible to detect disease-causing mutations in 56% of patients with adRP, roughly 30% of patients with recessive RP, and nearly 90% of patients with X-linked RP, which indicates that the there are several or many more RP genes that have yet to be discovered (Daiger et al. 2010).

The most common genes causing adRP are RHO (26-28% of all RP cases), PRPF31/RP11 (5-8%), PRPH2/RDS (4-8%), RP1 (6%), IMPDH1 (1-3%), KLHL7 (0.5-1.5%), NR2E3 (0.5-1.5%), PRPF3/RP18 (1%), PRPF8/RP13 (3%), CRX (1%) and TOPORS (1%) (Fahim et al. 2013; Daiger et al. 2010; Sullivan et al. 2013). The most common genes causing arRP are USH2A (10-15%), ABCA4 (2-5%), PDE6A (2-5%), PDE6B (2-5%), RPE65 (2-5%), and CNGA1 (1-2%). Considering only XLRP cases, pathogenic variants in RPGR account for the vast majority (~80%), with RP2 accounting for about 10% (Breuer et al. 2002; Sharon et al. 2003).

Among the RP genes, a few genes (BEST1, NR2E3, NRL, RDH12, RHO and RP1) have been reported to exhibit both ad and ar inheritance (Daiger et al. 2013).

The RP1 gene encodes a 2156 amino acid protein, which is localized in the connecting cilium and axoneme of photoreceptor sensory cilia. RP1 is a photoreceptor-specific microtubule-associated protein, which is essential for the correct localization and proper stacking of outer segment discs (Liu et al. 2003; Liu et al. 2004). Mutations in the RP1 gene account for ~5.5% adRP and ~1% of arRP cases (Chen et al. 2009). The inheritance mode is dependent on the type and position of the mutation (Siemiatkowska et al. 2012). Siemiatkowska et al. proposed that nonsense variants that occur in the “hot spot” region between amino acid residues 500-1053 of the RP1 protein act in a dominant negative manner to cause autosomal dominant RP. The missense variants that result in residual protein function and the protein-truncating variants near the 3′ end of the gene causes arRP (Siemiatkowska et al. 2012). Over 90 different RP1 pathogenic variants (missense, nonsense, small deletions, insertions and indels) have been reported (Human Gene Mutation Database).

Mutations in the RP1 gene account for ~5.5% adRP and ~1% of arRP cases (Chen et al. 2009).

To date, there have been no reported gross deletions or duplications in RP1 (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the RP1 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).