Retinal Cone Dystrophy 4
A number sign (#) is used with this entry because of evidence that retinal cone dystrophy-4 (RCD4) is caused by homozygous mutation in the CACNA2D4 gene (608171) on chromosome 12p13.
Clinical FeaturesWycisk et al. (2006) described 2 sibs with a recessive form of retinal cone dystrophy (RCD4). Symptoms were minimal except for slowly progressive reduction in visual acuity and moderate photophobia. Fundus examination showed nearly normal appearance in both. Color discrimination testing was consistent with defective color vision, and full-field electroretinography (ERG) showed moderately attenuated rod photoreceptor responses and markedly diminished cone responses. Although rod and cone ERGs suggested incomplete stationary night blindness, the authors noted that the disorder in these patients was progressive, not stationary, and concluded that their disease represented a mild cone dystrophy.
Ba-Abbad et al. (2016) described 2 unrelated women with retinal dysfunction and mutations in the CACNA2D4 gene (see MOLECULAR GENETICS). The first proband was a 22-year-old Indian woman (pedigree 20414) who had moderate myopic astigmatism, poor contrast perception, and inability to track fast-moving objects, whereas the second proband, a 41-year-old Ashkenazi Jewish Romanian woman (pedigree 17462), was emmetropic. Both probands had lifelong stable reduced visual acuity of approximately 20/30, low color discrimination, and photophobia noted at ages 18 years and 40 years. Retinal images were unremarkable. ERGs were stable over time in both patients and showed generalized predominantly inner retinal cone system dysfunction, and both had subnormal pattern ERGs. Possible rod dysfunction was noted in the second proband at follow-up. Family histories were negative for similarly affected individuals, although the second proband had 2 brothers and 2 sons who apparently had a red-green color defect.
Molecular GeneticsWycisk et al. (2006) screened the candidate gene CACNA2D4 (608171) in 34 patients with an initial diagnosis of night blindness, and identified homozygosity for a nonsense mutation (Y802X; 608171.0001) in 2 sibs with a slowly progressive cone disorder. The mutation segregated with disease in the family and was not found in 224 control chromosomes.
Using a panel of 164 known retinal disease genes, 88 candidate genes, and 32 retina-abundant microRNAs, Huang et al. (2015) screened exome data from 179 Chinese probands with retinal disease and identified a 42-year-old man with a diagnosis of cone-rod dystrophy who was homozygous for an R707H missense mutation in the CACNA2D4 gene. Although the variant was reported to have segregated with disease in the patient's family, minimal clinical information was provided, and functional analysis was not performed.
In 222 probands with retinal dysfunction, who were negative for likely pathogenic variants in 192 retinopathy-associated genes, Ba-Abbad et al. (2016) performed whole-genome sequencing and identified 2 unrelated women with nonprogressive cone dysfunction who were homozygous for a nonsense mutation (R628X; 608171.0002) and a large deletion/insertion (608171.0003), respectively.