Bradyopsia (Retinal Dysfunction) via the RGS9 Gene

Bradyopsia or RGS9/RGS9BP-associated retinopathy is a rare retinal dysfunction that is inherited in an autosomal recessive manner. It is clinically 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 was 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, less than 5 pathogenic variants (missense and nonsense) in RGS9 have been reported to cause bradyopsia (Michaelides et al. 2010. PubMed ID: 19818506; Nishiguchi et al. 2004. PubMed ID: 14702087; Human Gene Mutation Database). De novo variants have not been reported in either RGS9 or RGS9BP.

Mouse model studies suggested that RGS9 is required for normal inactivation of the cone phototransduction cascades (Lyubarsky et al. 2001. PubMed ID: 11262419). 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. 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 RGS9 gene is challenging due to genetic heterogeneity and the limited number of cases. All the documented causative variants are detectable by this NGS technology.

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 RGS9 gene plus 10 bases flanking noncoding DNA in all available transcripts in addition to 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).