Autosomal Recessive Retinitis Pigmentosa 69 (RP69) via the IMPG2 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).

Nonsyndromic RP is remarkably heterogeneous both clinically and genetically and exhibits autosomal dominant (AD), autosomal recessive (AR) or X-linked (XL) inheritance. To date, over 50 loci have been linked to nonsyndromic RP and 18, 27 and 2 genes have been identified that are associated with AD, AR, and XL RP, respectively (RetNet).

Pathogenic variants in IMPG2 have been documented causative for autosomal recessive (AR) Retinitis Pigmentosa (RP) with relatively early macular involvement (Bandah-Rozenfeld et al. 2010. PubMed ID: 20673862; van Huet et al. 2014. PubMed ID: 24876279) and autosomal dominant (AD) late-onset vitelliform macular dystrophy (Meunier et al. 2014. PubMed ID: 25085631).

IMPG2 and another gene IMPG1 encode the interphotoreceptor matrix proteoglycan 2 and 1, respectively. IMPG1 and IMPG2 are also known as sialoprotein associated with cones and rods (SPACR) and SPACRCAN (a proteoglyCan related to SPACR), respectively. These are large glycosylated protein components of the insoluble interphotoreceptor matrix (IPM). Both these proteins consist of hyaluronan (HA) binding motifs and it is believed that they bind to HA and that their interaction stabilizes or modulates the IPM scaffold (Brandl et al. 2017. PubMed ID: 28644393). To date, over 30 pathogenic variants (missense, nonsense, splicing, small frameshift deletions, insertions and a large deletion) in IMPG2 have been connected to retinal disorders (Human Gene Mutation Database). Of note, loss of function variants repeatedly have been reported in cases with AR inheritance (Brandl et al. 2017. PubMed ID: 28644393).

Predicting clinical sensitivity for the IMPG2 gene is challenging due to genetic heterogeneity. However, IMPG1 and IMPG2 are new causal genes in 8% of cases that are negative for BEST1 and PRPH2 causative variants (Meunier et al. 2014. PubMed ID: 25085631).

This test provides full coverage of all coding exons of the IMPG2 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).