Alternative titles; symbols
ORPHA: 1872; DO: 0111011;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 17p13.1 | Cone-rod dystrophy 6 | 601777 | Autosomal dominant; Autosomal recessive | 3 | GUCY2D | 600179 |
A number sign (#) is used with this entry because of evidence that cone-rod dystrophy-6 (CORD6) is caused by heterozygous mutation in the retinal guanylate cyclase gene (GUCY2D; 600179) on chromosome 17p13.
One patient with CORD6 has been reported with a homozygous mutation. Homozygous mutation in the GUCY2D gene usually causes Leber congenital amaurosis-1 (LCA1; 204000).
For a general phenotypic description and a discussion of genetic heterogeneity of cone-rod dystrophy, see 120970.
Small and Gehrs (1996) studied a family from eastern Tennessee in which 34 members in multiple generations had what the authors called 'autosomal dominant progressive cone degeneration.' Symptoms generally began in the first decade of life and slowly progressed into midlife. Ophthalmoscopic findings consisted primarily of macular granularity or central macular atrophy. The photopic full-field electroretinogram (ERG) was important in establishing the diagnosis, although the results of the ERG measurements varied among individuals. Either the foveal ERG amplitudes were abnormally low or the foveal/parafoveal ratio was abnormal in all affected individuals. The authors commented that no single test or finding was completely sensitive or specific for accurate diagnosis of the condition. Especially in the more mildly affected subjects, a constellation of symptoms, findings, and test results were used to diagnose autosomal dominant cone degeneration.
Gregory-Evans et al. (2000) described the clinical features of the family originally linked to CORD6 by Kelsell et al. (1997). In addition to childhood-onset clinical and electroretinographic features of CORD, moderate myopia and pendular nystagmus were seen in affected individuals. Of the 10 affected family members studied, an electroretinogram (ERG) was recordable in the 4 youngest (ages 14 to 47 years). In all 4 individuals, the cone ERG was more severely affected than the rod ERG. Color vision testing was possible in the youngest affected family member (age 14); it revealed no blue discrimination but retention of significant red-green discrimination. The authors concluded that the CRD phenotype associated with GUCY2D is clinically distinct from that associated with other dominant CRD loci. They postulated that the unusual electroretinographic responses may indicate that this mutation of GUCY2D is associated with early defects in photoreceptor synaptic transmission to second-order neurons.
Perrault et al. (1998) studied a family in which 6 members over 3 generations exhibited early cone dysfunction in the first decade of life, characterized by decreased vision acuity, severe color dyschromatopsia, and photophobia. At that stage, ophthalmoscopic examinations were not specific. In contrast, electrophysiologic testing revealed marked loss of photopic function, with scotopic function relatively well preserved, and the visual field showed a consistent central scotoma. During the second and third decades, visual acuity decreased dramatically, and the color vision defect consisted of achromatopsia, hampering normal schooling and vocational training. After the age of 40 years, peripheral visual field loss and progressive night blindness were observed, and the ERG became nonrecordable.
Ugur Iseri et al. (2010) reported a consanguineous Turkish family segregating autosomal recessive CORD, with 6 affected members over 2 generations. All affected individuals had dramatically reduced visual acuity, dyschromatopsia, and nyctalopia, together with variable presentation of photophobia, bone spicule formation, retinal vessel attenuation, retinal degeneration, and macular and chorioretinal atrophy with decreased cone and rod responses on ERGs. None of the patients was blind at birth, rather having reduced but stable vision loss according to family history.
Kelsell et al. (1997) performed genetic linkage analysis on a 4-generation British family with autosomal dominant cone-rod dystrophy. The disorder displayed an early onset, with loss of central vision reported before 7 years of age, progressing to the peripheral visual field later in life. Linkage was found with 8 marker loci situated on 17p13-p12. A maximum 2-point lod score of 5.93 with no recombination was obtained with marker locus D17S1844. Critical recombinants identified with flanking marker loci placed the disease gene in an estimated 8-cM interval. The localization for this disorder, designated CORD6 by them, overlapped with regions attributed previously to Leber congenital amaurosis, located at 17p13, central areolar choroidal dystrophy (215500), which has been mapped to 17p, and dominant cone dystrophy (600977), which has been mapped to 17p13-p12.
Small et al. (1996) demonstrated linkage to a region of chromosome 17p in the large eastern Tennessee family with 34 affected members. A lod score of 4.21 at theta = 0.04 was found with marker D17S796. They pointed out that the defect is in the general area of the recoverin gene (179618), which maps to 17p13.1 and is therefore an appealing candidate gene in this disorder. Udar et al. (2003) genotyped 38 affected and 32 unaffected members of the eastern Tennessee family with progressive cone dystrophy originally reported by Small and Gehrs (1996) and by haplotype analysis defined a critical interval between D17S938 and a marker they designated CORD5NU26 that contained the candidate GUCY2D gene.
In a 3-generation family segregating autosomal dominant cone-rod dystrophy, Perrault et al. (1998) obtained a maximum lod score of 2.71 at recombination fraction zero for 2 markers in the region of the GUC2D gene.
In a consanguineous Turkish family segregating autosomal recessive CORD, Ugur Iseri et al. (2010) obtained a genomewide multipoint lod score of 4.23 at chromosome 17p13.3-p11.2. Additional genotyping refined the locus to a 5.34-Mb interval between markers D17S1828 and D17S1791, with maximum 2-point and multipoint lod scores of 4.57 and 5.48, respectively.
In the British family originally reported by Kelsell et al. (1997) and in 3 unrelated families with cone-rod dystrophy, Kelsell et al. (1998) identified 2 different heterozygous mutations in the GUCY2D gene (600179.0005 and 600179.0006, respectively).
Udar et al. (2003) sequenced the entire GUCY2D gene in an affected individual from each of 2 families with cone dystrophy, 1 of which was the eastern Tennessee family originally reported by Small and Gehrs (1996), and identified a heterozygous mutation in each (600179.0006 and 600179.0008, respectively).
In affected members of a 3-generation family segregating autosomal dominant cone-rod dystrophy, Perrault et al. (1998) identified a complex mutation event involving 3 consecutive missense mutations within a single exon (600179.0007). The mutation was considered to represent a gene conversion event.
In affected members of a consanguineous Turkish family segregating autosomal recessive CORD mapping to chromosome 17p13.3-p11.2, Ugur Iseri et al. (2010) identified homozygosity for a missense mutation (600179.0010) in the GUCY2D gene.
Downes et al. (2001) described the phenotype and electrophysiologic responses in 4 British families, 3 with an R838C mutation (600179.0006) and 1 with an R838H mutation (600179.0008) in the GUCY2D gene. Although subjects had lifelong poor vision in bright light, a major reduction in visual acuity did not occur in most of them until after their late teens. Fundus abnormalities were confined to the central macula, and increasing central atrophy was noted with age. Electrophysiologic testing revealed a marked loss of cone function with only minimal rod involvement, even in older subjects. The authors concluded that the phenotype associated with autosomal dominant cone-rod dystrophy with either an R838C or R838H mutation in GUCY2D was distinctive, with predominantly cone system involvement. There was some variation in severity within the 3 families with the R838C mutation. Families with the R838C or R838H mutations had a much milder phenotype than the families previously described with the E837D/R838S mutation (600179.0005) in GUCY2D.
Downes, S. M., Payne, A. M., Kelsell, R. E., Fitzke, F. W., Holder, G. E., Hunt, D. M., Moore, A. T., Bird, A. C. Autosomal dominant cone-rod dystrophy with mutations in the guanylate cyclase 2D gene encoding retinal guanylate cyclase-1. Arch. Ophthal. 119: 1667-1673, 2001. [PubMed: 11709018] [Full Text: https://doi.org/10.1001/archopht.119.11.1667]
Gregory-Evans, K., Kelsell, R. E., Gregory-Evans, C. Y., Downes, S. M., Fitzke, F. W., Holder, G. E., Simunovic, M., Mollon, J. D., Taylor, R., Huntt, D. M., Bird, A. C., Moore, A. T. Autosomal dominant cone-rod retinal dystrophy (CORD6) from heterozygous mutation of GUCY2D, which encodes retinal guanylate cyclase. Ophthalmology 107: 55-61, 2000. [PubMed: 10647719] [Full Text: https://doi.org/10.1016/s0161-6420(99)00038-x]
Kelsell, R. E., Evans, K., Gregory, C. Y., Moore, A. T., Bird, A. C., Hunt, D. M. Localisation of a gene for dominant cone-rod dystrophy (CORD6) to chromosome 17p. Hum. Molec. Genet. 6: 597-600, 1997. [PubMed: 9097965] [Full Text: https://doi.org/10.1093/hmg/6.4.597]
Kelsell, R. E., Gregory-Evans, K., Payne, A. M., Perrault, I., Kaplan, J., Yang, R.-B., Garbers, D. L., Bird, A. C., Moore, A. T., Hunt, D. M. Mutations in the retinal guanylate cyclase (RETGC-1) gene in dominant cone-rod dystrophy. Hum. Molec. Genet. 7: 1179-1184, 1998. [PubMed: 9618177] [Full Text: https://doi.org/10.1093/hmg/7.7.1179]
Perrault, I., Rozet, J.-M., Gerber, S., Kelsell, R. E., Souied, E., Cabot, A., Hunt, D. M., Munnich, A., Kaplan, J. A retGC-1 mutation in autosomal dominant cone-rod dystrophy. (Letter) Am. J. Hum. Genet. 63: 651-654, 1998. [PubMed: 9683616] [Full Text: https://doi.org/10.1086/301985]
Small, K. W., Gehrs, K. Clinical study of a large family with autosomal dominant progressive cone degeneration. Am. J. Ophthal. 121: 1-12, 1996. [PubMed: 8554074] [Full Text: https://doi.org/10.1016/s0002-9394(14)70528-8]
Small, K. W., Syrquin, M., Mullen, L., Gehrs, K. Mapping of autosomal dominant cone degeneration to chromosome 17p. Am. J. Ophthal. 121: 13-18, 1996. [PubMed: 8554076] [Full Text: https://doi.org/10.1016/s0002-9394(14)70529-x]
Udar, N., Yelchits, S., Chalukya, M., Yellore, V., Nusinowitz, S., Silva-Garcia, R., Vrabec, T., Maumenee, I. H., Donoso, L., Small, K. W. Identification of GUCY2D gene mutations in CORD5 families and evidence of incomplete penetrance. Hum. Mutat. 21: 170-171, 2003. [PubMed: 12552567] [Full Text: https://doi.org/10.1002/humu.9109]
Ugur Iseri, S. A., Durlu, Y. K., Tolun, A. A novel recessive GUCY2D mutation causing cone-rod dystrophy and not Leber's congenital amaurosis. Europ. J. Hum. Genet. 18: 1121-1126, 2010. [PubMed: 20517349] [Full Text: https://doi.org/10.1038/ejhg.2010.81]