A number sign (#) is used with this entry because of evidence that cone-rod dystrophy-15 (CORD15), retinitis pigmentosa-65 (RP65), and retinal macular dystrophy-5 (MCDR5) can be caused by homozygous or compound heterozygous mutation in the CDHR1 gene (609502) on chromosome 10q23.

Cone-rod dystrophy-15 (CORD15) is characterized by onset of reduced vision in the third to fifth decades of life. Visual acuity progressively worsens, and most patients exhibit reduced color vision and central scotomas (Cohen et al., 2012; Sobolewska et al., 2023). Retinitis pigmentosa-65 (RP65) is an adult-onset form of RP, with night blindness developing in the second to fourth decades of life. In addition to constriction of visual fields, patients may experience photophobia, reduced visual acuity, and difficulties with color vision (Henderson et al., 2010; Bessette et al., 2018; Dawood et al., 2021). Retinal macular dystrophy-5 (MCDR5) is a late-onset form of macular dystrophy, with most patients noting symptoms in the fourth to sixth decades of life. Symptoms include reduced visual acuity, glare, poor contrast vision, and metamorphopsia; night blindness is uncommon (Stingl et al., 2017; Charbel Issa et al., 2019; Ba-Abbad et al., 2021). Macular atrophy is a characteristic feature in all patients, and early involvement may be observed even in patients with RP who exhibit relatively preserved visual acuity (Malechka et al., 2022).

For a general phenotypic description and a discussion of genetic heterogeneity of cone-rod dystrophy, see 120970; for retinitis pigmentosa, see 268000; for retinal macular dystrophy, see 136550.

Reviews

Bessette et al. (2018) reviewed published reports of patients with disease-causing mutations in the CDHR1 gene. The median age of patients was 36 years, and the majority retained visual acuity of 20/70 or better in at least one eye. Most patients developed symptoms between the first and third decades of life (range, infancy through fourth decade). Night blindness was the most common presenting symptom (54%), followed by photosensitivity (39%) and decreased vision (31%). Macular atrophy was the most common fundus feature reported (96%), followed by vascular attenuation (69%) and peripheral bone spicules (54%). The authors noted significant inter- and intrafamilial phenotypic variability among patients with CDHR1 mutations.

Cone-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 and mutation in the CDHR1 gene. 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.

Cohen et al. (2012) reported 2 sisters from a consanguineous Israeli Christian Arab family (TB127) with cone-rod dystrophy and mutation in the CDHR1 gene. The affected sisters first noticed impaired day vision in their twenties, and electroretinography showed absent cone responses with markedly reduced rod responses. Pattern visual evoked potentials showed reduced waveforms and prolonged implicit time, indicating severely reduced macular function. In the fourth decade of life, visual acuity was markedly decreased and color vision was severely impaired. Visual field testing showed bilateral deep large central scotomas, as well as significant general reduction of sensitivity, and optical coherence tomography revealed bilateral severe thinning of the macula. Funduscopy showed pink optic discs and moderately attenuated retinal vessels, as well as macular atrophy with lack of macular reflex. One sister (IV:2, age 36) showed no pigmentary changes, whereas her older sister (IV:3, age 38) showed beaten-bronze pigmentary changes in the macula, and a few bone spicule-like pigmentation deposits and punctate salt- and pepper-like appearance in the peripheral retina.

Sobolewska et al. (2023) studied a 49-year-old Polish man with cone-rod dystrophy and mutation in the CDHR1 gene. He reported gradual reduction in visual acuity over 5 years; examination showed best-corrected visual acuity (BCVA) of 20/50 in the right eye and 20/20 in the left. Color vision was normal. Funduscopy showed an atrophic area around the optic discs, macular degeneration, and retinal thinning bilaterally. Visual field testing demonstrated a central scotoma with preserved peripheral vision bilaterally. Enhanced depth-imaging optical coherence tomography revealed foveal thinning with distortion and loss of the outer nuclear layer, external limiting membrane, ellipsoid zone, and retinal pigment epithelium bilaterally. Fundus fluorescein angiography revealed granular hyperfluorescence in the macula and concomitant areas of capillary atrophy. Flash full-field electroretinography showed lowering of a and b waves as well as prolonged peak time in light-adapted conditions; however, dark-adapted responses were normal.

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.

Bessette et al. (2018) reported a retrospective case series involving 4 patients with retinal dystrophy and mutation in the CDHR1 gene. An 65-year-old man (case 1) and an unrelated 39-year-old woman (case 2) presented with night blindness and generalized constriction of visual fields, and showed pale optic nerves, arteriolar attenuation, and bone-spicule pigmentation in the midperipheral retina on funduscopy. Visual acuity was 20/30 in case 1 and 20/50 in case 2. A milder phenotype was observed in 2 affected sisters: the younger sister (case 3), age 43, was asymptomatic when diagnosed at age 30 with macular dystrophy due to macular spots seen on routine eye exam. She developed problems with dark adaptation at age 35 and had mild nasal constriction of visual fields, normal visual acuity and color vision, and bulls-eye-like changes in the macula with a ring of atrophic retinal pigment epithelium (RPE) surrounding the fovea. The older sister (case 4), age 48, had been told she had 'signs of macular dystrophy' on routine eye exam at age 18. She had simultaneous onset of difficulties with dark adaptation, color vision, and light sensitivity at age 44. Visual acuity was 20/50 bilaterally, and she had mild constriction of visual fields, mild disc pallor, and diffuse RPE atrophy in the macula and periphery, with rare bone-spicule pigmentation.

Dawood et al. (2021) reported a large consanguineous Pakistani family (family 2) with RP and mutation in the CDHR1 gene. The 8 affected individuals ranged in age from 12 years to 51 years old, with night blindness and reduced visual acuity as prominent features in all. Examination revealed classic RP features, including pale waxy disc, attenuated retinal vessels, and bone-spicule pigmentation bilaterally. In addition, affected individuals exhibited evidence of macular atrophy. The authors noted a wide range of severity among the affected family members.

Retinal Macular Dystrophy 5

Stingl et al. (2017) reported 13 patients from 9 families with retinal disease and biallelic mutations in the CDHR1 gene, including 4 diagnosed with RP, 6 diagnosed with cone-rod dystrophy, and 3 patients (patients D, E, and H) who exhibited a form of cone dystrophy with primarily macular involvement and normal rod responses on ERG. Patients E and H had no history of night blindness, and patient D reported only a very slight subjective night blindness. The authors noted that the retinal presentation was heterogeneous, but that all 13 patients had macular involvement, and the macula showed changes regardless of disease duration.

Charbel Issa et al. (2019) studied 10 patients with CDHR1-associated retinopathy, including 6 patients (group 1) homozygous for the same synonymous mutation (c.783G-A, P261P; 609502.0005) who exhibited a macula-predominant retinal phenotype resembling central areolar choroidal dystrophy (CACD). Symptoms appeared in the fifth to sixth decades of life, and included reduced visual acuity, difficulties reading, glare, poor contrast vision, and metamorphopsia; none of the patients in group 1 had night blindness. The remaining 4 patients, 2 of whom were compound heterozygous for the c.783G-A variant and a truncating mutation (group 2) and 2 of whom had biallelic truncating and/or splice site mutations (group 3), did report night blindness. Funduscopy in group 1 patients showed an early bulls-eye macular appearance with foveal sparing and mild pigmentary changes; later disease stages showed a sharply demarcated atrophy of the retinal pigment epithelium within the macula, but normal-appearing peripheral retina and retinal vessels. Group 2 and 3 patients showed more widespread fundus changes including hypopigmentation and narrowing of retinal vessels, with bone-spicule pigmentation in the most severe case. All but 1 of the patients had onset of symptoms in the fifth decade of life, indicating a late onset for CDHR1-related retinal dystrophies. The authors considered the phenotype in group 1 to represent a form of CACD, which they designated 'CACD5,' whereas group 3 patients had cone-rod dystrophy and group 2 had an 'intermediate phenotype.'

Ba-Abbad et al. (2021) reviewed the records of 7 patients from 6 pedigrees with late-onset macular dystrophy and mutation in the CDHR1 gene, including 6 patients who were homozygous or compound heterozygous for the previously reported c.783G-A variant. Onset of symptoms was in the fourth to sixth decade of life, and BCVAs ranged from 20/15 to 20/200. Autofluorescence (AF) imaging showed macular flecks of increased AF in mild cases, and patches of reduced AF in severe cases; OCT showed attenuation of the ellipsoid zone (EZ) in mild cases and loss of the EZ and outer nuclear layer in severe cases. The full-field ERG was normal or borderline subnormal in all cases, and the pattern ERG was subnormal in mild cases and undetectable in severe cases.

Malechka et al. (2022) reported a cohort of 10 patients with retinal dystrophy and mutation in the CDHR1 gene. Age at onset of symptoms ranged from 5 years to 45 years, and severity of symptoms was also quite variable. Cone-rod dystrophy was diagnosed in 6 patients, rod-cone dystrophy in 3 patients, and late-onset macular degeneration (LOMD) in 1 patient. Loss of visual acuity was the most common presenting symptom, and in all 3 groups of patients, macular atrophy was a characteristic feature: all patients presented with early macular involvement, even in the setting of rod-cone dystrophy and relatively preserved visual acuity, and the degree of macular atrophy did not seem to correlate with age. The authors suggested that LOMD could be characterized as a milder spectrum-extending finding within the CDHR1 retinopathy presentation.

Ostergaard 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.

In a consanguineous Israeli Christian Arab family (TB127) with cone-rod dystrophy, Cohen et al. (2012) performed genomewide homozygosity mapping and identified several homozygous intervals shared between the 2 affected sisters, including 1 interval containing the candidate gene CDHR1.

In 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.

In a consanguineous Israeli Christian Arab family (TB127) with cone-rod dystrophy, Cohen et al. (2012) sequenced the CDHR1 gene and identified homozygosity for a splice site mutation (609502.0004) in the 2 affected sisters. The mutation was present in heterozygosity in 2 unaffected sibs, and was not found in 208 ethnically matched control chromosomes, or in the 1000 Genomes Project database. In addition, the mutation was not found in 6 unrelated Israeli Christian Arab families with cone-rod dystrophy, suggesting that it represents a rare private mutation.

Stingl et al. (2017) reported 13 patients from 9 families with retinal disease and biallelic mutations in the CDHR1 gene, including 6 diagnosed with cone-rod dystrophy, 4 diagnosed with RP (1 of whom, patient G, was previously reported by Glockle et al., 2014 as patient 924), and 3 patients who exhibited a form of cone dystrophy (MCDR5; see 613660) with primarily macular involvement and normal rod responses on ERG (see, e.g., 609502.0005-609502.0008). The authors noted that the retinal presentation was heterogeneous, but that all 13 patients had macular involvement, and the macula showed changes regardless of disease duration. Intrafamilial variability was observed. The authors stated that genotype/phenotype correlations were unclear because a number of the patients carried 2 different mutations, and functional analysis of missense mutations was not performed.

In a retrospective case series of patients presenting with retinal dystrophy, Bessette et al. (2018) identified 4 patients who were homozygous or compound heterozygous for the previously reported c.783G-A mutation in the CDHR1 gene (609502.0005). The variant was found in homozygosity in 2 unrelated patients with RP (cases 1 and 2), and was present in compound heterozygosity with a splice site variant in CDHR1 in 2 sisters (cases 3 and 4) with a milder retinal dystrophy phenotype. Segregation analysis and functional studies were not reported. The authors suggested that homozygosity for the c.783G-A variant might be associated with a more severe phenotype.

Charbel Issa et al. (2019) reported 6 patients from 5 families with slowly progressive macular atrophy (MCDR5; see 613660) who were homozygous for the CDHR1 c.783G-A variant, which segregated with disease in the families for which relatives' DNA was available. Although the mutation is predicted to result in a synonymous substitution (P261P), functional analysis using patient whole blood RNA demonstrated aberrant splicing with in-frame skipping of exon 8. Noting that the variant was present in the gnomAD database at a relatively high minor allele frequency (0.31%), with 5 homozygotes, the authors suggested that the relatively mild and late-onset phenotype might mean that those individuals were in the presymptomatic stage of disease, or that there is incomplete penetrance of c.783G-A homozygosity, or that modifiers contribute to the phenotype. The authors also identified 4 patients with CORD phenotypes, 2 of whom were compound heterozygous for the c.783G-A variant and truncating mutations in CDHR1, and 2 of whom were homozygous or compound heterozygous for truncating mutations in CDHR1. The authors concluded that c.783G-A represents a mild hypomorphic mutation, resulting in disease essentially restricted to the macula, whereas biallelic truncating mutations lead to retina-wide cone-rod dystrophy with severe function loss. Noting that homozygosity for the c.783G-A variant previously had been reported in patients with a diagnosis of RP (Stingl et al., 2017; Bessette et al., 2018), the authors stated that the reason for the considerable phenotypic difference remained unclear.

Ba-Abbad et al. (2021) reviewed the clinical records of patients with macular dystrophy and biallelic variants in the CDHR1 gene, and identified 1 woman (family GC24117) who was homozygous for the c.783G-A variant, as well as 5 more patients from 4 families (GC17748, GC26788, GC20637, and GC27924) who were compound heterozygous for c.783G-A and another mutation in CDHR1. A seventh patient (GC26837) was compound heterozygous for a missense mutation and a splice site mutation. The authors concluded that genotypes distinct from those causing panretinal dystrophy could cause a milder phenotype, predominantly affecting the macula, and suggested that the macula might be susceptible to mild perturbations of the photoreceptor cadherin.

In 8 affected individuals from a multiply consanguineous Pakistani family (family 2) with RP, who were negative for known variants in ocular disease-associated genes, Dawood et al. (2021) analyzed exome data and identified homozygosity for a splice site mutation the CDHR1 gene (609502.0009). Sanger sequencing confirmed the mutation, which was either not found or present in heterozygosity in the 9 unaffected family members tested. The mutation was not found in the gnomAD database.

In a cohort of 10 patients with retinal dystrophy, including 6 diagnosed with cone-rod dystrophy, 3 with rod-cone dystrophy, and 1 with late-onset macular degeneration, Malechka et al. (2022) identified homozygosity or compound heterozygosity for mutations in the CDHR1 gene (see, e.g., 609502.0005 and 609502.0010). The authors stated that a genotype-phenotype correlation could not be established due to the small size of the cohort and the multiplicity of CDHR1 variants carried by patients in all 3 groups.

In a 49-year-old Polish man with cone-rod dystrophy, Sobolewska et al. (2023) identified homozygosity for the previously reported c.783G-A mutation in the CDHR1 gene.