Bradyopsia (Retinal Dysfunction) via the RGS9BP Gene

Bradyopsia or RGS9/R9AP-associated retinopathy is a rare retinal dysfunction characterized by reduced central vision from childhood due to cone dysfunction, mild photophobia, normal color vision, lack of nystagmus, normal fundi and distinctive electrophysiologic features (Michaelides et al. 2010. PubMed ID: 19818506). The chief complaint of all patients is difficulty tracking moving objects and adapting to sudden changes in luminance levels. Walking out of a house into the sunlight for example causes temporary severe blindness (Kooijman et al. 1991. PubMed ID: 1790747).

With the advent of gene therapy and other types of treatments, the identification of causative genes and variants is becoming increasingly important.

Pathogenic variants in either RGS9 (encoding a GTPase-activating protein) or RGS9BP (encoding its membrane anchor protein) have been identified in patients with autosomal recessive bradyopsia or RGS9/RGS9BP-associated retinopathy (Strauss et al. 2015. PubMed ID: 26343007). Both genes play a critical role in the recovery phase of visual transduction (Strauss et al. 2015. PubMed ID: 26343007; Nishiguchi et al. 2004. PubMed ID: 14702087). To date, about 5 pathogenic variants (small deletions and duplications and an entire gene deletion) in RGS9BP have been connected to bradyopsia (Michaelides et al. 2010. PubMed ID: 19818506; Human Gene Mutation Database). De novo variants have not been reported in either RGS9 or RGS9BP.

In both RGS9 and R9AP knockout mice, a small delay was observed in ON-bipolar cell light responses manifested as delayed onset of electroretinography b-waves was. This is consistent with the prolonged electroretinal response suppression (PERRS) in the Bradyopsia patients (Herrmann et al. 2011. PubMed ID: 22096596; Kooijman et al. 1991. PubMed ID: 1790747).

Predicting clinical sensitivity for the RGS9BP gene is challenging due to genetic heterogeneity and the limited number of cases.

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

This test provides full coverage of the single coding exon of the RGS9BP 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).