Autosomal Recessive Retinitis Pigmentosa via the FLVCR1 Gene

Retinitis pigmentosa (RP) or rod cone dystrophies (RCDs) represent a group of hereditary retinal dystrophies with a worldwide prevalence of ~1 in 4000 (Booij et al. 2005). 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). FLVCR1-associated RP is characterized by posterior column ataxia and retinitis pigmentosa (Rajadhyaksha et al. 2010).

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 involved with AD RP, AR RP, and XL RP, respectively (RetNet). Pathogenic variants in FLVCR1 have been documented causative for AR RP (Liu et al. 2015). FLVCR1-encoded protein is a mammalian heme transporter with highest expression in the retina. This protein is required for erythroid differentiation, indicating that heme export is important in primary cells at this stage to protect them from heme toxicity (Quigley et al. 2004; Rajadhyaksha et al. 2010). So far, about 10 pathogenic variants (missense, splicing and small deletions) have been reported in FLVCR1-associated RP (The Human Gene Mutation Database).

Sensitivity data are limited. Mutation screening in a cohort of 20 Chinese families affected by autosomal recessive inherited retinal dystrophy, identified homozygous and biallelic variants in 11 of the 20 families (55%). Out of the 11 families, one family had causative variants in FLVCR1 (5%) (Liu et al. 2015).

This test provides full coverage of all coding exons of the FLVCR1 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).