Cone-Rod Dystrophy 15
A number sign (#) is used with this entry because this form of cone-rod dystrophy (CORD15) can be caused by homozygous mutation in the CDHR1 gene (609502) on chromosome 10q23. An adult-onset form of retinitis pigmentosa (RP65) can also be caused by homozygous mutation in the CDHR1 gene.
For a general phenotypic description and a discussion of genetic heterogeneity of cone-rod dystrophy, see 120970.
For a general phenotypic description and a discussion of genetic heterogeneity of retinitis pigmentosa, see 268000.
Clinical FeaturesCone-Rod Dystrophy 15
Ostergaard et al. (2010) studied 6 affected members of a 3-generation consanguineous pedigree from the Faroe Islands segregating autosomal recessive cone-rod dystrophy. The 3 oldest affected sibs reported decreased vision from around 17 years of age. In addition to cone-rod dystrophy, 2 of 3 sibs from the youngest generation also had oculocutaneous albinism (OCA; see 203100), which caused nystagmus and reduced visual acuity from early infancy. The genetic background for their albinism was unknown, but no mutations were found by sequencing the TYR (606933) or OCA2 (611409) genes. Retinal examination of all 6 patients showed both central and peripheral pigment abnormalities. The foveal changes consisted of irregular pigmentation and atrophy of the retinal pigment epithelium (RPE) with a horizontal oval-shaped or ill-defined 'moth-eaten' appearance. In the 2 patients with OCA, the changes in the foveal regions were less obvious due to the scarcity of pigment. The peripheral pigment disturbances included diffuse RPE atrophy and black hyperpigmentations of polymorphic shape, some of which were filiform and sheeted the vessels. The amount of pigmentation varied considerably among patients of the same age but showed some correlation to the extent of visual field constriction. In the oldest patients, the optic discs looked moderately atrophic, and the retinal vessels were universally constricted. Visual field measurements showed considerable variation, with some patients having normal or only slightly constricted outer field limits. Color vision was severely impaired in the 2 patients tested.
Retinitis Pigmentosa 65
Henderson et al. (2010) studied 2 families with an adult-onset form of autosomal recessive retinitis pigmentosa (arRP), consisting of a retinal dystrophy that began late in the second decade of life with nyctalopia and visual field defects, and by the fourth decade resulted in significantly impaired central vision. The first family was a 2-generation consanguineous family of Middle Eastern descent, in which there were 4 affected and 2 unaffected sibs, ranging in age from 32 to 42 years. Nyctalopia was first reported in the late teenage years, and photophobia occurred in the middle of the third decade of life. Visual acuity was 0.1 (LogMAR) in the fourth decade, deteriorating to hand movements by the fifth decade. All affected family members had a severe color vision defect, and all had a low myopic refractive error. Fundus examination revealed vessel attenuation, diffuse retinal pigment epithelial changes, and sparse bone spicule pigment migration in the retinal periphery in the younger patients. With disease progression, there was dense pigment migration and atrophy both at the macula and in the periphery. Electroretinography (ERG) in the 3 oldest patients showed both rod and cone responses; the ERG in the youngest affected family member was consistent with a 'mild cone-rod dystrophy.' In the second family, only 1 affected member was available for study. He had onset of night blindness at 18 years of age. Upon examination at 30 years of age, his visual acuity was 0.2 (LogMAR) bilaterally, but deteriorated to hand movements by 46 years of age. Color vision was abnormal at the initial examination, and fundus findings showed early RPE depigmentation at the macula at age 32 years. Later there were circular patches of pigment epithelial atrophy both at the macula and in the periphery associated with pigment migration and vessel attenuation. ERG at age 34 years revealed no detectable rod or cone responses in either eye.
MappingOstergaard et al. (2010) performed genomewide homozygosity mapping in 6 patients from a 3-generation consanguineous Faroese pedigree segregating autosomal recessive cone-rod dystrophy and identified a single homozygous region on chromosome 10q23.1-q23.2, for which multipoint linkage analysis yielded a lod score of 3.1. The 4.2-Mb linkage interval was flanked by heterozygous markers rs6584455 and rs868042.
In a 2-generation consanguineous Middle Eastern family segregating arRP, Henderson et al. (2010) performed a genomewide linkage scan and identified a 10-cM region on chromosome 10q23.1-q23.3 for which all 4 affected sibs were homozygous and their unaffected parents and sibs were heterozygous. In another family with arRP, the largest region of autozygosity was also on chromosome 10q.
Molecular GeneticsIn a 3-generation consanguineous Faroese pedigree segregating autosomal recessive cone-rod dystrophy mapping to 10q23.1-q23.2, Ostergaard et al. (2010) analyzed 3 candidate genes and identified homozygosity for a 1-bp insertion in the PCDH21 gene (CDHR1; 609502.0001) in all affected individuals. The mutation was present in heterozygosity in 12 unaffected family members, and 2 other unaffected family members did not carry the mutation. Screening of 159 Faroese controls revealed 3 heterozygous carriers, corresponding to a carrier frequency of 1.9%.
In a 2-generation consanguineous Middle Eastern family segregating autosomal recessive retinitis pigmentosa (arRP) mapping to chromosome 10q23.1-q23.3, Henderson et al. (2010) analyzed 3 candidate genes and identified homozygosity for a 1-bp deletion in the CDHR1 gene (609502.0002) in the 4 affected sibs. The deletion was not found in the unaffected parents or sibs, or in 60 ethnically matched controls, 86 UK blood donors, or a panel of DNA from 192 patients with arRP and 96 patients with Leber congenital amaurosis (LCA; see 204000). In the proband from a second consanguineous family with arRP, direct sequencing of CDHR1 revealed homozygosity for a different 1-bp deletion (609502.0003) that was not found in controls. Henderson et al. (2010) noted that the youngest affected individual had a cone-rod pattern of disease on electroretinography, suggesting that the earliest manifestation of mutations in CDHR1 is a cone-rod dystrophy.