Cone-Rod Dystrophy 18
A number sign (#) is used with this entry because of evidence that cone-rod dystrophy-18 (CORD18) is caused by homozygous mutation in the RAB28 gene (612994) on chromosome 4p15.
For a general phenotypic description and a discussion of genetic heterogeneity of cone-rod dystrophy (CORD), see 120970.
Clinical FeaturesRoosing et al. (2013) studied a German family in which 3 sibs were diagnosed with cone-rod dystrophy in the second decade of life, with rapidly deteriorating visual acuities and high myopia. Funduscopy showed hyperpigmentation of the fovea, and autofluorescence revealed a slightly hyperfluorescent fovea. Optical coherence tomography (OCT) showed altered photoreceptors in the fovea but intact peripheral photoreceptors. Color-vision tests revealed defects in all axes, and visual field testing showed a central scotoma. On electroretinography (ERG), photopic responses were nondetectable and scotopic responses reduced in all 3 sibs. Roosing et al. (2013) also studied a consanguineous family of Moroccan Jewish origin in which a brother and sister with CORD had a presentation similar to that of the sibs from the German family. The brother presented with low vision from early childhood, with progressive deterioration of visual acuity and high myopia. The retinal pigment epithelium showed foveal atrophy; hypofluorescence was observed in the fovea and a hyperfluorescent ring was noted around the fovea. OCT imaging confirmed absence of photoreceptors in the central fovea, whereas the photoreceptor layer further out appeared largely intact. Color-vision defects were noted in both sibs. Photopic ERG responses were nondetectable, and scotopic responses were moderately reduced.
Riveiro-Alvarez et al. (2015) reported 2 unrelated patients of Spanish descent with childhood onset of CORD. Both patients had markedly reduced visual acuity, bull's eye maculopathy, foveal hyperpigmentation, peripapillary atrophy, dyschromatopsia, extinguished photopic ERG responses, and reduced scotopic ERG responses. One patient had high myopia and diplopia.
Molecular GeneticsIn 2 of 3 affected sibs from a German family with CORD, Roosing et al. (2013) performed exome sequencing but found no pathogenic variants in known autosomal recessive CORD-associated genes among the shared variants; there was only a single homozygous shared variant, a nonsense mutation in the RAB28 gene (E189X; 612994.0001), located within the largest shared homozygous region in the family. Sanger sequencing confirmed homozygosity for the mutation in the 3 affected sibs, and it was not found in 176 ethnically matched controls or in the Exome Variant Server database (ESP6500). Sequencing of RAB28 in 468 CORD probands and 149 probands with cone dystrophy revealed no mutations. Analysis of SNP data from more than 400 probands in the European Retinal Disease Consortium, including patients with autosomal recessive CORD, Leber congenital amaurosis (see 204000), and retinitis pigmentosa (see 268000), identified 7 families with large homozygous regions spanning RAB28; Sanger sequencing of RAB28 in those families revealed a homozygous nonsense mutation (R137X; 612994.0002) in affected sibs from a consanguineous family of Moroccan Jewish ancestry with CORD.
By whole-exome sequencing in 2 unrelated patients of Spanish ancestry with CORD who did not have mutations in the ABCA4 gene (601691), Riveiro-Alvarez et al. (2015) identified homozygosity for a splice site (615374.0003) and a missense (615374.0004) mutation in the RAB28 gene, respectively. The mutations segregated with the disorder in the families. Neither mutation was found in the 1000 Genomes Project or Exome Variant Server databases or in an internal control database of 6,250 exomes. Sanger sequencing of RAB28 in 107 additional patients of Spanish descent with CORD revealed no mutations.