Cone-Rod Dystrophy 16
A number sign (#) is used with this entry because of evidence that retinal dystrophy, including a form of cone-rod dystrophy (CORD16) and a form of retinitis pigmentosa (RP64), can be caused by homozygous or compound heterozygous mutation in the C8ORF37 gene (614477) on chromosome 8q22.
Mutation in C8ORF37 can also cause Bardet-Biedl syndrome (BBS21; 617406), in which retinal dystrophy is associated with other features.
For a general phenotypic description and a discussion of genetic heterogeneity of cone-rod dystrophy (CORD), see 120970; for a similar discussion regarding retinitis pigmentosa (RP), see 268000.
DescriptionCone-rod dystrophy (CORD) and retinitis pigmentosa (RP) are clinically and genetically overlapping heterogeneous retinal dystrophies. RP is characterized initially by rod photoreceptor dysfunction, giving rise to night blindness, which is followed by progressive rod and cone photoreceptor dystrophy, resulting in midperipheral vision loss, tunnel vision, and sometimes blindness. In contrast to RP, CORD is characterized by a primary loss of cone photoreceptors and subsequent or simultaneous loss of rod photoreceptors. The disease in most cases becomes apparent during primary-school years, and symptoms include photoaversion, decrease in visual acuity with or without nystagmus, color vision defects, and decreased sensitivity of the central visual field. Because rods are also involved, night blindness and peripheral vision loss can occur. The diagnosis of CORD is mainly based on electroretinogram (ERG) recordings, in which cone responses are more severely reduced than, or equally as reduced as rod responses (summary by Estrada-Cuzcano et al., 2012).
Clinical FeaturesEstrada-Cuzcano et al. (2012) studied 4 unrelated consanguineous families with retinal dystrophy. Four patients from 2 families were diagnosed with cone-rod dystrophy, and 2 patients from 2 families were diagnosed with retinitis pigmentosa with early macular involvement. Age at presentation ranged from infancy to late teens. The patients all showed early involvement of the macula, resulting in loss of central vision at an early age: none had visual acuity better than 20/60 and 1 patient had light perception only. All showed attenuation of retinal vessels, and the CORD patients had temporal optic disc pallor and some pigment clumping, whereas the RP patients had bone spicule-like pigmentation and waxy optic disc. Rod and cone patterns were nonrecordable by electroretinography (ERG) in the 2 RP patients and in 2 of the CORD patients; in the other 2 CORD patients, the cone pattern was nonrecordable and the rod recording was severely reduced. A brother and sister with CORD also had postaxial polydactyly: each had an extra finger or toe on the right hand or foot, respectively.
Ravesh et al. (2015) reported 5 individuals with isolated RP from 2 unrelated families (MA13 and MA48) of Pakistani origin. All affected individuals had early-onset RP with moderate to severe loss of visual acuity between the second and third decades of life. Full-field ERG was unrecordable in the proband from family MA13, and 1 patient from family MA48 had sluggish pupillary reactions consistent with a severe form of RP with a minimally functioning retina. No extraocular manifestations were observed in the examined patients.
Katagiri et al. (2016) described a Japanese brother and sister who had loss of visual acuity during childhood. On initial examination at ages 43 years and 37 years, respectively, both patients showed severely decreased visual acuity, high myopia, chorioretinal degeneration with macular atrophy, severely constricted visual fields, and nonrecordable ERG responses. In addition, the sister had severe nuclear cataracts and the brother had nuclear and subcapsular cataracts. The retinal degeneration and visual field constriction progressed during follow-up. Neither patient exhibited obesity, polydactyly, renal dysfunction, cardiovascular disorders, hyperlipidemia, or impaired glucose tolerance. Katagiri et al. (2016) stated that this early-onset retinal dystrophy could not be classified as either RP or CORD because of the severe retinal degeneration at initial presentation and because loss of visual acuity and night blindness were reported to have occurred in the same period of childhood.
Rahner et al. (2016) reported 2 sisters of Moroccan origin who had CORD with postaxial polydactyly but no other features of BBS. Impaired vision was first noted at 5 to 6 years of age, and ERGs in the second decade of life showed absent cone response with markedly reduced rod response. Pattern visual evoked potentials indicated severely reduced macular function, and color vision was markedly impaired. Optical coherence tomography showed bilateral severe thinning of the macula. Funduscopy in the older sister revealed a pale optic disc, mildly attenuated retinal vessels, atrophy of the retinal pigment epithelium, and spicule-like pigmentation deposits in the periphery. In the younger sister, only sporadic round pigmentary changes in the periphery were observed. The older sister also exhibited postaxial polydactyly of both feet and the left hand, whereas the younger sister had postaxial polydactyly only of the left foot.
Molecular GeneticsIn the proband from a consanguineous family, who had retinitis pigmentosa with early macular involvement, Estrada-Cuzcano et al. (2012) performed genomewide homozygosity mapping followed by targeted next-generation sequencing and identified a homozygous nonsense mutation in the C8ORF37 gene (614477.0001) on chromosome 8q22.1. Analysis of C8ORF37 in 15 consanguineous families with retinal dystrophy revealed homozygosity for 1 splice site and 2 missense mutations in affected individuals from 3 families, respectively, 2 with cone-rod dystrophy (614477.0002; 614477.0003) and 1 with RP (614477.0004). Two affected sibs from 1 of the families also had postaxial polydactyly; Estrada-Cuzcano et al. (2012) noted that the Bardet-Biedl ciliopathy syndrome (209900) also includes both polydactyly and retinal dystrophy.
In a consanguineous family (MA48) of Pakistani origin with RP, Ravesh et al. (2015) sequenced the candidate gene C8ORF37, previously implicated in retinal dystrophy and located within an approximately 14.4-Mb homozygous interval on chromosome 8, and identified homozygosity for a splice site mutation (614477.0005) in all 3 affected brothers. Whole-exome sequencing in another RP family (MA13) of Pakistani origin revealed homozygosity for a nonsense mutation in C8ORF37 (W185X; 614477.0006) in the affected sister and brother. Both mutations segregated with disease in the respective families, and neither was found in 8,244 South Asian exomes in the ExAC database.
By whole-exome sequencing in a Japanese family in which a brother and sister had early-onset severe retinal degeneration that could not be classified as RP or CORD, Katagiri et al. (2016) identified compound heterozygosity for a splice site mutation and a 1-bp deletion in the C8ORF37 gene.
In a consanguineous family of Moroccan origin with CORD and postaxial polydactyly, Rahner et al. (2016) identified 3 regions of homozygosity that were present in the 2 affected sisters but not in their unaffected sibs, and obtained the maximum lod score expected in this family, 2.6, for all 3 regions. Sequence analysis of the only recessive CORD-associated gene located within a homozygous interval, C8ORF37, revealed homozygosity for a splice site mutation in both affected sisters (614477.0008). The mutation was present in heterozygosity in their first-cousin parents and 13 other unaffected family members, and was not found in the 1000 Genomes database. Reviewing previously reported patients with mutations in C8ORF37, Rahner et al. (2016) noted that in both families in which patients exhibited CORD associated with postaxial polydactyly, the affected individuals had splice site mutations involving intron 1, at the splice donor and splice acceptor site, respectively. However, the authors found no correlation between mutation location and the ocular phenotype of RP or CORD.