A number sign (#) is used with this entry because of evidence that Leber congenital amaurosis-12 (LCA12) is caused by homozygous mutation in the RD3 gene (180040) on chromosome 1q32.

For a general phenotypic description and a discussion of genetic heterogeneity of LCA, see LCA1 (204000).

Leber congenital amaurosis-12 (LCA12) is characterized by congenital nystagmus, low vision, sluggish pupillary reflexes, absence of ocular pursuit from birth, early onset and long-lasting digitoocular signs of Franceschetti, and mild to moderate hyperopia. Photoaversion is usually present. Visual acuity, when measurable, is reduced to counting fingers, hand movements, or light perception (summary by Perrault et al., 2013).

Friedman et al. (2006) identified a sister and brother with Leber congenital amaurosis from a consanguineous Indian family. Both probands had had poor vision since birth. Nystagmus and atrophic lesions in the macular area with pigment migration were found on examination.

Preising et al. (2012) reported a large consanguineous Kurdish family with LCA, in which 6 of 7 affected individuals were available for study. All patients reported glare sensitivity and exhibited severe nystagmus. Pupillary reactions, which were always present, were sluggish in the index patient at his first examination at 4 months of age. Visual acuity decreased over time, resulting in light perception only; initial refraction was hypermetropic and became myopic over the course of the disease. Funduscopy before 2 years of age was unremarkable but later showed attenuated vessels and macular changes that progressed from loss of the macular wall reflex to a bull's-eye lesion with central yellow pigment in childhood. By the third decade of life, the patient had a peripheral fundus with a hammer-beaten appearance that later displayed bone spicules. Fundus autofluorescence, obtainable in only 1 patient at 7 years of age, was strongly reduced within the macula, diffusely increased in a broad ring around the macula, and faded toward the periphery. Optical coherence tomography (OCT) at a young age showed disorganization of all retinal layers; later OCT recordings revealed preservation of the external limiting membrane, although it was severely displaced, with a marked reduction in thickness of the outer and inner plexiform layers and the inner nuclear layer. Thinning of the ganglion cell and nerve fiber layers was also observed. The visual fields that could be measured in 5 patients showed a severe reduction, to 20 degrees or less. Electroretinographic responses in the 4 patients tested were nonrecordable.

Perrault et al. (2013) studied 9 patients from 7 unrelated families with mutations in the RD3 gene. Patients consistently presented with congenital nystagmus, low vision, sluggish pupillary reflexes, absence of ocular pursuit since birth, early-onset and long-lasting digitoocular sign of Franceschetti, photoaversion, and mild to moderate hyperopia. Visual acuity, when measurable, was reduced to counting fingers, hand movements, or light perception. Examination of the fundus consistently showed dull retina with salt-and-pepper aspect, thin retinal vessels, and early macular rearrangement (maculopathy). In 1 patient for whom OCT findings were available, the photoreceptor layer was missing, the inner/outer segment border was diminished, and an increased backscatter from the choroid was observed due to atrophy of the retinal pigment epithelium (RPE), in contrast to the relatively preserved inner retinal layers. Fundus autofluorescence was so severely reduced that no image could be produced.

In a large consanguineous Kurdish family with LCA, Preising et al. (2012) performed genomewide SNP analysis and obtained a lod score of 3.627 at chromosome 1q31-q32 (chr1:209,473,694-214,664,986, GRCh37). Recombination events narrowed the region of interest.

The transmission pattern of LCA12 in the family reported by Friedman et al. (2006) was consistent with autosomal recessive inheritance.

In 881 probands with retinal dystrophy from North America, the United Kingdom, India, and Scandinavia, Friedman et al. (2006) sequenced all coding exons and flanking intron/exon boundaries of the RD3 gene and identified homozygosity for a donor splice site mutation (180040.0001) in a sister and brother from a consanguineous Indian family.

In a large consanguineous Kurdish family with LCA mapping to chromosome 1q32, Preising et al. (2012) directly sequenced the RD3 gene and identified homozygosity for a nonsense mutation (Y60X; 180040.0002) that segregated with disease in the family. Analysis of 85 unrelated patients with severe early-onset retinal dystrophy did not reveal any more causative RD3 mutations. Preising et al. (2012) concluded that sequence changes in the RD3 gene are a very rare cause of LCA that are associated with an extremely severe form of retinal dystrophy.

Using DNA samples from 852 unrelated patients ascertained worldwide with LCA or early-onset severe retinal degeneration, Perrault et al. (2013) screened the RD3 gene and identified homozygosity for 3 truncating mutations in 7 probands from consanguineous families: the same nonsense mutation (R38X; 180040.0003) was detected in 9 affected individuals from 5 families originating from the southern shores of the Mediterranean (2 Moroccan, 2 Turkish, and 1 Lebanese); a 2-bp deletion (180040.0004) in an Algerian woman; and another nonsense mutation (E46X; 180040.0005) in a Mexican girl. Perrault et al. (2013) noted phenotypic overlap between LCA12 and LCA1, which is caused by mutation in the GUCY2D gene (600179).