X-linked Retinitis Pigmentosa (XLRP) via the RP2 Gene

Retinitis pigmentosa (RP) refers to a group of related eye disorders stemming from the degeneration of photoreceptor cells in the retina (Pagon and Daiger, 2005). RP derives its name from retinal pigmentation changes. In RP patients, pigment granules accumulate in perivascular clusters, called bone spicules, in the retinal pigment epithelium (RPE). The accumulation of pigment is typically accompanied by death of the photoreceptor cells, first rods and eventually cones. As a result, RP will often present first with night blindness and decreased peripheral vision due to systematic loss of rod cells, followed by deterioration of central vision acuity and day blindness from the loss of cone cells. RP has an incidence of ~1/3500 and can be inherited in autosomal recessive, autosomal dominant, X-linked, digenic and even mitochondrial patterns. Currently, variants in over 30 genes are known to cause RP.

X-linked RP (XLRP) is one of the most severe forms of RP, with early onset and rapid progression in males. Milder symptoms can also present in females, probably due to random X inactivation. At least five different genetic loci have been associated with XLRP: Xp11.2 (RP2), Xp21.1 (RPGR), Xp21.2-21.3 (RP6), Xp22 (RP23), and Xp26-27 (RP24) (http://www.sph.uth.tmc.edu/RetNet/disease.htm). To date, only the RP2 and RPGR genes have been identified. RPGR encodes the retinitis pigmentosa GTPase regulator (Meindl et al. Nat Genet 13:35-42, 1996), and RP2 encodes a protein of unknown function (Schwahn et al. 1998). Variants in RPGR account for the vast majority (~80%) of all XLRP cases while RP2 accounts for about 10% of cases and the other loci likely account for the remainder (~10%) (Breuer et al. 2002; Sharon et al. 2003). The RP2 gene consists of 5 exons with variants found throughout all five exons; no founder variants or mutational hotspots have been reported. Most variants result in premature protein termination (i.e. frameshift, nonsense, and splice-site), although a few missense variants have also been identified (Mears et al. 1999; Hardcastle et al. 1999). Males hemizygous for variants in RP2 typically display classic features of RP, such as initial night blindness and loss of peripheral vision. Patients with variants in RP2 appear to retain less visual acuity than patients with variants in RPGR (Sharon et al. 2003). Thus, knowledge of which XLRP gene is mutated is useful for making the most accurate long-term visual prognosis.

This test is predicted to detect a causative variant in ~10-20% of all patients with presumptive XLRP (Breuer et al. Am J Hum Genet 70:1545-1554, 2002; Sharon et al. Am J Hum Genet 73:1131-1146, 2003).

This test provides full coverage of all coding exons of the RP2 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).