In a 4-generation consanguineous family with retinitis pigmentosa studied by Nishimura et al. (2010), the phenotype was variable in that 6 of 8 affected individu...
In a 4-generation consanguineous family with retinitis pigmentosa studied by Nishimura et al. (2010), the phenotype was variable in that 6 of 8 affected individuals had adult-onset RP, whereas 2 patients had a much earlier onset of disease, at less than 5 years of age, and had severe generalized dystrophy associated with nystagmus.
Collin et al. (2010) described 4 Dutch sibs from a large pedigree, originally reported by Pinckers et al. (1973), segregating autosomal dominant granular corneal dystrophy, autosomal recessive retinal degeneration, and intermediately transmitted albinism. The 4 affected sibs were the only family members who manifested retinal degeneration, consisting of a photoreceptor dystrophy resembling RP or rod-cone dystrophy in most aspects. All patients complained of night blindness and demonstrated characteristic ophthalmoscopic abnormalities such as peripheral bone spicules and attenuated retinal vessels. However, there was also evidence of early degeneration of the cone photoreceptor system, exemplified by macular abnormalities in all 4 patients and by ERGs in 2 of them, in which cone function appeared to be slightly more affected than rod function, although both were severely damaged. With night blindness, relatively good visual acuity, and mild color vision disturbances, as well as ring scotoma on the visual field in 1 patient, Collin et al. (2010) considered the diagnosis to be 'somewhat atypical' RP. A decade later, ERGs in the 2 patients were nonrecordable, and visual acuity in all 4 patients deteriorated to finger counting and light perception over the next 2 decades.
Nishimura et al. (2010) performed homozygosity mapping using SNP genotyping in 5 individuals from a consanguineous family segregating nonsyndromic arRP and identified an approximately 8-Mb region of shared homozygosity at chromosome 2p24.1-p23.1, between SNPs rs2339705 and rs2303324. Parametric linkage analysis yielded a maximum lod score of 4.5 for this region. In a second arRP family, mapping identified a single 21.8-Mb region of homozygosity encompassing the chromosome 2 region found in the first family; the common 8-Mb interval contained 90 genes, none of which were known to cause isolated retinitis pigmentosa.
Collin et al. (2010) performed homozygosity mapping in 4 Dutch sibs with retinitis pigmentosa and affected members of 2 Muslim Arab Israeli families segregating arRP and identified a combined region of homozygosity, a 5.9-Mb segment between rs12470303 and rs10514769 on chromosome 2p24.1-p23.1.
▼ Molecular Genetics
In affected members of 2 consanguineous families segregating arRP mapping to chromosome 2p24.1-p23.1, Nishimura et al. (2010) sequenced the candidate gene C2ORF71 (613425) and identified homozygosity for a nonsense mutation (W253X; 613425.0001) and a missense mutation (I201F; 613425.0002), respectively. The mutations segregated with disease and were not detected in 100 and 102 ethnically matched controls, respectively.
In 1 Dutch and 2 Muslim Arab Israeli families with arRP mapping to chromosome 2p24.1-p23.1, Collin et al. (2010) identified 3 homozygous loss-of-function mutations in the C2ORF71 gene that segregated with disease in each family, respectively, and were not found in ethnically matched controls (613425.0003-613425.0005).
Khateb et al. (2014) reported a large consanguineous family of Iranian Jewish origin (MOL0028) in which 6 sibs had early-onset severe sensorineural hearing loss, 3 of whom also had relatively mild retinal degeneration (see CRDHL2, 618358) and 3 of whom had early-onset severe RP. The sibs with severe RP in addition to hearing loss were double homozygotes, for a nonsense mutation (Q1097X) in the C2ORF71 gene, and a nonsense mutation in the CEP250 gene (609689.0001). The authors concluded that the severe retinal involvement in the double homozygotes indicated an additive effect caused by nonsense mutations in 2 genes encoding ciliary proteins.