Retinitis Pigmentosa via the PRPH2 (RDS) Gene

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 variants 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 PRPH2/RDS gene encodes a transmembrane glycoprotein expressed in vertebrate photoreceptors. It is localized to the rim of the disc membranes of the photoreceptor outer segments and helps in folding and stacking of the discs (Kohl et al. 1998). After the RHO gene, PRPH2 is one of the major causative genes for adRP (accounts for 4-8% of cases) (Fahim et al. 2013; Daiger et al. 2010; Sullivan et al. 2013). Over 90 different PRPH2 pathogenic variants (missense, nonsense, splicing, small and gross deletions, insertions and small indels) have been reported (Human Gene Mutation Database).

After the RHO gene, PRPH2 is one of the major causative genes for adRP (accounts for 4-8% of cases) (Fahim et al. 2013; Daiger et al. 2010; Sullivan et al. 2013). A relatively high frequency of PRPH2 pathogenic variants (23%) was found in 61 unrelated autosomal dominant macular dystrophy (adMD) Spanish families (Gamundi et al. 2007).

Gross deletions or duplications in PRPH2 have only been rarely reported (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the PRPH2 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).