Heon Yung Gee, R. G. Coussa, R. Faingold, Robert K. Koenekoop, Arif O. Khan, Jacek Majewski, Edgar A. Otto, Huanan Ren, Vafa Keser, Jeremy Schwartzentruber, Irma Lopez, Q. Fu, P. Arthurs, and Friedhelm Hildebrandt
Retinitis pigmentosa (RP) is a well known inherited retinal dystrophy that leads to progressive loss of vision, and eventually complete blindness due to photoreceptor cell death. RP is restricted to the eye, specifically the retina and photoreceptors. Its prevalence is estimated to be at 1/4000 (1–3). RP is caused by progressive loss of rods followed by the loss of cones. Affected individuals start experiencing night blindness in the first two decades of life. Peripheral visual field constriction leads to ‘tunnel vision’, progressive loss of visual acuity (VA) leads to complete loss of all vision (4). On fundus exam, RP is classically characterized by retinal atrophy, optic nerve head pallor, vascular narrowing and a variety of peripheral retinal pigmentary deposits including bone spicules. RP can be restricted to the eye (non-syndromic) or a retinal degeneration indistinguishable from RP can be associated with a syndrome. The syndromic features can be very obvious or very subtle. Also, the syndromic features can be present at the time of diagnosing the retinal degeneration, or they may appear much later. Examples are Bardet–Biedl syndrome (BBS), Usher Syndrome (USH) and Senior-Loken Syndrome (SLS). The mode of inheritance of RP may be autosomal dominant [autosomal dominant retinitis pigmentosa (adRP); 5–25%], autosomal recessive [autosomal recessive retinitis pigmentosa (arRP); 5–20%], rarely digenic, mitochondrial or X-linked [Xlinked retinitis pigmentosa (xlRP); 5–15%] (5). There are currently 36 genes implicated in arRP that only explain ~50% of the cases (RetNet), illustrating that many mutations and new genes still need to be discovered. RPE65, which is expressed in the retinal pigment epithelium (RPE), PDE6A and PDE6B, which are both phosphodiesterase subunits in the phototransduction cascade, EYS and USH2A, are among the most well-known or common genetic etiologies (5, 6). Interestingly, several genes associated with RP (in patients without systemic disease) can also be mutated in syndromic disorders such as BBS1 and USH2 (7, 8) and SLS which is an autosomal recessive disease affecting primarily the kidney and retina, leading to nephronophthisis (NPHP) and RP, respectively (9). Of particular interest in RP and these syndromes is the emergence of a group of genes and proteins that function in and are localized to the cilium, the so-called ciliary genes. In photoreceptor outer segments (OS, which represent modified cilia), the stacked discs house the proteins for visual function with several important RP ciliary gene products, e.g. RPGR, RPGRIP1, USH2A, CEP290, LCA5, and TULP1. We identified an atypical form of arRP in a French-Canadian family (Fig. 1) and excluded mutations in all the known arRP genes. We hypothesized that this family carries mutations in a novel RP specific gene and subsequently identified homozygous mutations in WDR19. At the time of discovery (August 2011), there was no published article in the literature linking this gene to any human disease and specifically to arRP. On re-evaluation of this family, we discovered that several of the RP patients had sub-clinical renal cysts, which prompted us to hypothesize that this gene may be mutated in RP patients with frank kidney failure, a disorder coined SLS. We then performed mutation analysis in this gene in a cohort of patients with RP in Quebec and a cohort with the syndromic form of RP, namely SLS and identified more RP families and several SLS families with mutations. At this time, both Bredrup et al. in their original article and Huber et al., in their review article, described the involvement of WDR19, a ciliary gene, in a variety of ciliopathies including Sensenbrenner, Jeune syndrome and isolated NPHP (10, 11). Similarly, Halbritter et al. reported the first case of Caroli disease, which is a rare inherited disorder most commonly characterized by congenital cystic dilatation of the intrahepatic biliary ducts secondary to ectasia, caused by mutations in WDR19. However, there is yet no study confirming clearly the involvement of WDR19 in arRP as well as in SLS (12). Fig. 1 (a) Family A pedigree. (b) Retinal photo showing an atrophic maculopathy and severe narrowing of the blood vessels and temporal pallor of the optic nerve head. (c) Fundus autofluorescence showing the ‘bear claw’ maculopathy and hypo-fluorescence ... In the process of identifying a novel gene for RP and SLS, we also identified a novel genotype–phenotype correlation in the arRP families. We illustrate that the combined use of Arrayed Primer Extension (APEX) technology, homozygosity mapping by single nucleotide polymorphism (SNP) genotyping and next generation sequencing (NGS), can rapidly and reliably lead to new gene discovery.