Autosomal Recessive Retinitis Pigmentosa 66 (RP66) via the RBP3 Gene

Retinitis pigmentosa (RP) represents a group of hereditary retinal dystrophies with a worldwide prevalence of ~1 in 4,000 (Booij et al. 2005. PubMed ID: 16272259). 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. 1999. PubMed ID: 10025514).

RBP3-associated RP has onset of central vision loss in adult life with or without night blindness. The disease onset ranged from 32 to 60 years of age (den Hollander et al. 2009. PubMed ID: 19074801). A different study reported that the affected individuals presented childhood onset high myopia symptoms at a much younger age (8–14 years) (Arno et al. 2015. PubMed ID: 25766589).

Pathogenic variants in RBP3 (alternatively known as IRBP) have been documented causative for autosomal recessive Retinitis pigmentosa (Arno et al. 2015. PubMed ID: 25766589; den Hollander et al. 2009. PubMed ID: 19074801). To date, ~20 pathogenic variants (missense, nonsnse and small frameshift deletions) in RBP3 have been associated with RP (Human Gene Mutation Database; Arno et al. 2015. PubMed ID: 25766589; den Hollander et al. 2009. PubMed ID: 19074801). No de novo pathogenic variants have been reported.

RBP3 encodes Interphotoreceptor retinoid-binding protein (IRBP). The IRBP protein greatly enhances the conversion of all-trans-retinol to 11-cis-retinaldehyde by the retinal pigment epithelium (RPE) in the visual cycle. IRBP also facilitates the removal of 11-cis-retinaldehyde from the RPE (Edwards and Adler. 2000. PubMed ID: 10655150; Qtaishat et al. 2005. PubMed ID: 15935345). Mouse model studies demonstrated that the absence of RBP3 leads to loss of photoreceptor nuclei and changes in the structural integrity of the receptor outer segments at postnatal day 11. At 30 day of age, the photoreceptor abnormalities were more severe. These results suggest that the absence of RBP3 gene results in a slowly progressive degeneration of retinal photoreceptors (Liou et al. 1998. PubMed ID: 9614228). A different study showed that the insertion of the HEL (hen egg lysozyme) transgene in the photoreceptor membrane disrupted the normal photoreceptor function, which was associated with the reduced levels of soluble IRBP protein (Liu et al. 2018. PubMed ID: 29571629). RBP3 has been cited as a nonessential gene for growth of human tissue culture cells (Online Gene Essentiality, ogee.medgenius.info).

Less than 1% of RP cases are due to pathogenic variants in RBP3 (Fahim et al. 1993. PubMed ID: 20301590).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the RBP3 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).