Focused Inherited Retinal Disorders Panel

Inherited retinal disorders (IRD) are the leading cause of blindness in the western world (1 in 3000 people). Identifying the genetic cause for the IRD is challenging due to genetic heterogeneity. According to the World Health Organization (WHO) and the American Academy of ophthalmology (AAO), ~ 80% of blindness can be prevented or cured or the disease progression could be slowed if detected at early stages. Given these statistics, the importance of early and accurate diagnosis cannot be understated. Currently, molecular diagnosis of the IRD is gaining importance due to the emerging treatments such as gene therapy (Sahel et al. 2014. PubMed ID: 25324231; Chen et al. 2013. PubMed ID: 23661368).

Identifying the genetic cause for the IRD is challenging due to genetic heterogeneity. So far, ~300 loci have been mapped and over 250 genes have been identified to be associated with retinal disorders (RetNet). This panel tests AIPL1, PCARE (C2orf71), CABP4, CEP290, CHM, CNGA1, CRB1, CRX, EYS, GUCY2D, IMPDH1, IQCB1, KCNJ13, LCA5, LRAT, NMNAT1, NR2E3, OTX2, PDE6A, PDE6B, PRPF8, RD3, RDH12, RDH5, RHO, RP1, RPE65, RPGRIP1, SPATA7, TULP1 and USH2A.

Pathogenic variants in AIPL1, CABP4, CEP290, CNGA1, EYS, IQCB1, LCA5, LRAT, NMNAT1, PCARE, PDE6A, RD3, RPGRIP1, SPATA7, TULP1 and USH2A cause autosomal recessive (AR) retinal disorders (Chen et al. 2013. PubMed ID: 23661368). Pathogenic variants in PRPF8, and OTX2 cause autosomal dominant (AD) retinal disorders (Bowne et al. 2006. PubMed ID: 16384941; Henderson et al. 2009. PubMed ID: 19956411; Swaroop et al. 1999. PubMed ID: 9931337; Zhao et al. 2006. PubMed ID: 16612614). CRB1, CRX, GUCY2D, IMPDH1, PDE6B, RDH5, RDH12, RP1, KCNJ13, RHO, NR2E3 and RPE65 are implicated in both AD and AR retinal disorders (Kohl et al. 2012. PubMed ID: 22901948; Piri et al. 2005. PubMed ID: 15629837; Wang et al. 2013. PubMed ID: 23847139; Weleber et al. 1993. PubMed ID: 8240110; Udar et al. 2003. PubMed ID: 12552567; Hanein et al. 2002. PubMed ID: 12325031; McKay et al. 2005. PubMed ID: 15623792; Abouzeid et al. 2006. PubMed ID: 16543197; Swaroop et al. 1999. PubMed ID: 9931337. 1999; Hejtmancik et al. 2008. PubMed ID: 18179896). Pathogenic variants in CHM are associated with X-linked choroideremia (van den Hurk et al. 2003. PubMed ID: 12827496). Pathogenic variants in these genes also cause other retinal disorders (Weleber. 2002. PubMed ID: 12187427; Wang et al. 2015. PubMed ID: 26047050; Wang et al. 2013. PubMed ID: 23847139; Online Mendelian Inheritance in Man; Human Gene Mutation Database).

See individual gene test descriptions for information on molecular biology of gene products and spectra of pathogenic variants.

Clinical sensitivity for the AIPL1 (4-8%), CEP290 (20%), CRB1 (10%), CRX (3%), GUCY2D (21%), LCA5 (1-2%), RDH12 (4%), RPE65 (3-16%), RPGRIP1 (5%), TULP1 (1.7%) genes is known (Weleber et al. 2013). The most common genes involved in autosomal recessive (AR) Retinitis Pigmentosa (RP) are USH2A (10-15%), PDE6A (2-5%), PDE6B (2-5%), RPE65 (2-5%), and CNGA1 (1-2%). PCARE and RHO each account for less than 1% of RP cases (Fahim et al. 2013. PubMed ID: 20301590). The most common genes involved in autosomal dominant (AD) RP are RHO (26-28% of RP cases), RP1 (6%), NR2E3 (0.5-1.5%), and PRPF8/RP13 (3%) (Fahim et al. 2013. PubMed ID: 20301590; Daiger et al. 2010. PubMed ID: 20238032; Sullivan et al. 2013. PubMed ID: 23950152). However, for other genes, due to the limited number of cases, estimation of clinical sensitivity is difficult (Hanein et al. 2004. PubMed ID: 15024725; Weleber et al. 2013. PubMed ID: 20301475). Together these genes account for 70-75% of the Leber Congenital Amaurosis cases (Wang et al. 2015. PubMed ID: 26047050; den Hollander et al. 2008. PubMed ID: 18632300).

A study by Perrault et al. (2000) identified two gross deletions and one duplication in GUCY2D out of 118 patients affected with Leber Congenital Amaurosis (Perrault et al. 2000. PubMed ID: 10951519). Copy number variants have also been reported in CEP290, CHM, CRB1, CRX, EYS, GUCY2D, LCA5, MERTK, NMNAT1, PDE6B, PRPF8, RDH12, RHO, RPE65, RPGRIP1, 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 99.7% 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).

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).