Retinitis Pigmentosa Panel

Retinitis pigmentosa (RP) represents a group of hereditary retinal dystrophies with a worldwide prevalence of ~1 in 4000 (Booij 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).

Nonsyndromic and syndromic RP is remarkably heterogeneous both clinically and genetically and exhibits autosomal dominant (AD, 15%-25% of the cases), autosomal recessive (AR, 5%-20% of the cases) or X-linked (XL, 5%-15% of the cases) inheritance (Fahim et al. 2013). Unknown, simplex cases (single occurrence in a family) account for 40%-50%of cases and rarely digenic inheritance has been reported (Fahim et al. 2013). To date, over 80 genes have been linked to RP (RetNet; Daiger et al. 2007; Daiger et al. 2013; Audo et al. 2012; Neveling et al. 2012; Fu et al. 2013; Zhao et al. 2015; http://www.omim.org/; Human Gene Mutation Database), but likely more RP genes remain to be discovered (Daiger et al. 2010; Daiger et al. 2013; Perez-Carro et al. 2016).

The most common genes involved in AD RP are RHO (26-28% of RP cases), PRPF31/RP11 (5-8%), PRPH2/RDS (4-8%), RP1 (6%), IMPDH1 (1-3%), KLHL7 (0.5-1.5%), NR2E3 (0.5-1.5%), PRPF3/RP18 (1%), PRPF8/RP13 (3%), CRX (1%) and TOPORS (1%) (Fahim et al. 2013; Daiger et al. 2010; Sullivan et al. 2013).

The most common genes involved in AR RP are USH2A (10-15%), ABCA4 (2-5%), PDE6A (2-5%), PDE6B (2-5%), RPE65 (2-5%), and CNGA1 (1-2%). BEST1, PCARE (C2ORF71), C8ORF37, CLRN1, CNGB1, DHDDS, FAM161A, IDH3B, IMPG2, LRAT, MAK, MERTK, NRL, PDE6G, PRCD, PROM1, RBP3, RGR, RHO, RLBP1, RP1, SAG, SPATA7, TTC8, CERKL, TULP1, ZNF513, and ARL6 each account for less than 1% of RP cases (Fahim et al. 2013).It has been reported that it is now possible to detect disease-causing variants in about 56% of patients with adRP, 30% of patients with recessive RP, and nearly 90% of patients with X-linked RP, which indicates that the there are several or many more RP genes that have yet to be discovered (Daiger et al. 2010).See individual gene test descriptions for more information on molecular biology of gene products.

It is now possible to detect disease-causing pathogenic variants in about 56% of patients with AD RP, 30% of patients with recessive RP, and nearly 90% of patients with X-linked RP (Daiger et al. 2010).

Genomic rearrangements in PRPF31 (causative for AD RP) are now known to account for 2.5% of AD RP (Sullivan et al. 2006). Deletions and rearrangements are also found in ABCA4, which is causative for AR RP (Yatsenko et al. 2003). In addition, copy number variants have been reported in ABHD12, ARL6, BEST1, CACNA1F, CEP290, CHM, CRB1, CRX, EYS, GUCY2D, IMPG2, MERTK, NR2E3, PDE6B, PRPF31, PRPH2, RDH12, RHO, RLBP1, RP2, RPE65, RPGR, RPGRIP1, SAG, SPATA7, TULP1 and USH2A (Human Gene Mutation Database).

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

This panel typically provides 99.1% coverage of all coding exons of the genes 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 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).

Analysis of RPGR exon 15 (commonly referred to as ORF15) has historically been difficult due to the highly repetitive, purine-rich sequence. When NGS does not achieve full coverage or there is a variant detected by NGS that needs confirmation, then we utilize a specialized chemistry Sanger sequencing.

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).