RPE65-Associated Disorders via the RPE65 Gene

Leber Congenital Amaurosis 2 (LCA2) or Severe Early Childhood-Onset Retinal Dystrophy (SECORD) and Retinitis Pigmentosa (RP20) associated with RPE65 pathogenic variants are due to dysfunction and degeneration of photoreceptors (Cideciyan et al. 2013. PubMed ID: 23341635; Weleber et al. 2011. PubMed ID: 20811047). All affected patients have night blindness, a typical and early symptom. LCA2 or SECORD and RP20 are characterized by profound vision loss at birth, variable degrees of nystagmus, high hypermetropia, photodysphoria, oculodigital signs, keratoconus, cataracts and variable appearance to the fundus (Chung and Traboulsi. 2009. PubMed ID: 20006823). Ophthalmoscopy reveals attenuated vessels, atrophy of the optic disc and many whitish dots due to extensive retinal pigment epithelium (RPE) defects (Gu et al. 1997. PubMed ID: 9326941). The estimated prevalence of LCA is 2-3 per 100,000 live births and accounts for 10-18% of congenital blindness (Fazzi et al. 2003. PubMed ID: 12615170). Several clinical features of LCA overlap with those of RP (Perrault et al. 1996. PubMed ID: 8944027; Daiger et al. 2007. PubMed ID: 17296890; Gu et al. 1997. PubMed ID: 9326941). Both LCA and RP are clinically and genetically heterogeneous.

LCA is inherited as an autosomal recessive trait in the vast majority of patients, while RP is either sporadic or familial with various modes of Mendelian, mitochondrial or oligogenic inheritance. To date, 14 and 25 genes have been implicated in LCA and autosomal recessive RP (AR-RP), respectively (den Hollander et al. 2008. PubMed ID: 18632300; Daiger et al. 2007. PubMed ID: 17296890). Of note, a pathogenic missense variant in RPE65 was identified by whole-exome sequencing in an autosomal dominant retinitis pigmentosa (with choroidal involvement) affected large Irish family (Bowne et al. 2011. PubMed ID: 21654732). Also, some RPE65 null allele heterozygous carriers may manifest visual symptoms (Felius et al. 2002. PubMed ID: 11786058). The clinical overlap between LCA and RP is illustrated by the involvement of six genes in both conditions. These include RPE65 (Marlhens et al. 1997. PubMed ID: 9326927; Gu et al. 1997. PubMed ID: 9326941), which encodes retinol isomerase, expressed in retinal pigment epithelium (RPE). Retinol isomerase is involved in vitamin A metabolism in the visual cycle to synthesize 11-cis-retinaldehyde. Pathogenic variants in this gene lead to no chromophore production and affect the visual pigments (Weleber et al. 2011. PubMed ID: 20811047).

RPE65 pathogenic variants account for approximately 8% of LCA and have been shown to be influenced by genetic background, environment and other factors (Li et al. 2009. PubMed ID: 18936139). About 30 different RPE65 pathogenic variants have been reported each in patients with LCA2 and RP20. LRAT, RPE65 and RDH12 pathogenic variants lead to similar phenotypes, suggesting the need to screen all these genes systematically (Sénéchal et al. 2006. PubMed ID: 17011878; Weleber et al. 2013. PubMed ID: 20301475). RPE65 pathogenic variants include missense, nonsense, splicing, and small deletions/insertions (mostly frameshift); they are distributed throughout the entire coding region.

A preliminary assessment with 176 probands from 9 different countries suggested that few patients affected with Leber Congenital Amaurosis (LCA) exhibit pathogenic variants in RPE65, indicating that LCA is extremely genetically heterogeneous (Lotery et al. 2000. PubMed ID: 10766140). In another study, RPE65 pathogenic variants accounted for ~2% (3 out of 162 cases) of recessive or isolate Retinitis Pigmentosa and ~16% (7 of 45) of LCA cases (Morimura et al. 1998. PubMed ID: 9501220). Thus far, only one gross deletion has been reported involving RPE65 (Al-Gazali and Ali. 2010. PubMed ID: 20437613).

This panel provides 100% coverage of all coding exons of the RPE65 gene, plus ~10 bases of flanking noncoding DNA. We define coverage as ≥20X NGS reads or Sanger sequencing.