Retinitis Pigmentosa via the NR2E3 Gene

Nonsyndromic retinitis pigmentosa (RP, OMIM 268000) is a large group of inherited degenerative diseases of the retina characterized by abnormalities of the photoreceptors or the retinal pigment epithelium. It is a progressive disease. Symptoms usually begin with night blindness, progressing to constriction of the peripheral visual field with eventual loss of central vision. The age of onset varies from childhood to middle age (Gu et al. J Med Genet 36:705-707, 1999). The clinical hallmarks are an abnormal fundus with bone-spicule deposits and attenuated retinal vessels, abnormal electroretinographic findings, and reduced visual fields (Daiger et al. Arch Ophthalmol 125:151-158, 2007). RP affects 1 in 3,000 people worldwide (Farrar et al. EMBO J 21:857-864, 2002). Genetic abnormalities are the primary cause of RP.

Retinitis pigmentosa (RP) is genetically and clinically heterogeneous. At least four distinct subgroups are recognized on the basis of the mode of inheritance and age of onset. These include autosomal dominant (AD-RP), autosomal recessive (AR-RP), X-linked, and digenic (Kajiwara et al. Science 264:1604-1608, 1994). In addition, RP can be inherited as a mitochondrial trait (Mansergh et al. Am J Hum Genet 64:971-985, 1999). Genetic heterogeneity is documented within each subgroup. About 50 % of patients with RP are isolated cases with no known affected relatives. It is unclear how many of these are real isolated cases caused by de novo variants or inherited with low penetrance. RP affects all ethnic groups, although variants in particular genes have been identified in specific populations. Currently, variants in 18 and 23 genes are known to cause AD-RP and AR-RP, respectively. These include the NR2E3 gene, which is also involved in enhanced S cone dystrophy (ESCS, Haider et al. Nat Genet 24:127-131, 2000). Recently, two novel NR2E3 variants have been implicated in RP. The first (p.Gly56Arg) was reported in two Belgian families and one French family with AD-RP (Coppieters et al. Am J Hum Genet 81:147-157, 2007). All affected individuals shared a common disease haplotype. In addition, they shared a similar phenotype, which corresponds to the classic RP phenotype accompanied by specific characteristics of ESCS. Briefly, this phenotype is characterized by a decline of rod function followed by that of cone function, as is usually the case in AD-RP, and by three concentric rings of hyperautofluorescence: around the fovea, along the vascular arcades and in the far periphery, with the two more central rings located in the same area as those affected in ESCS (Marmor et al. Am J Ophthalmol 110:124-134, 1990). The second variant (c.1038del) was reported in three siblings with AR-RP (Bernel et al. Clin Genet 73:360-366, 2008).

The NR2E3 gene is expressed specifically in the outer layer of the human retina and encodes a retinal nuclear receptor.

The p.Gly56Arg variant alone accounts for ~ 1-2% of AD-RP (AI Gire et al. Mol Vis 13:1970-1975, 2007). However, comprehensive information on sensitivity is not available yet.

This test provides full coverage of all coding exons of the NR2E3 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.