A number sign (#) is used with this entry because of evidence that cone-rod dystrophy-20 (CORD20) is caused by homozygous or compound heterozygous mutation in the POC1B gene (614784) on chromosome 12q21.

For a general phenotypic description and a discussion of genetic heterogeneity of cone-rod dystrophy (CORD), see 120970.

Roosing et al. (2014) studied a Turkish family in which 3 sibs had cone or cone-rod dystrophy. The proband presented in infancy with reduced visual acuity and mild nystagmus. At 9 years of age, she had a tritan defect of her color vision, and electroretinography (ERG) showed absent cone function but normal rod function, consistent with a diagnosis of incomplete achromatopsia (ACHM; see 216900). However, her visual acuity deteriorated over the next several years, and 2 of her younger sibs experienced rapid loss of central vision, suggesting a diagnosis of cone dystrophy (COD; see 602093) in the 2 sibs and CORD in the proband. Roosing et al. (2014) also studied a Dutch man who was diagnosed with ACHM in childhood based on the classic signs of reduced visual acuity, photophobia, nystagmus, very poor color vision, and typical ERG responses. However, in his fifth decade, visual acuity began to decrease, and in his sixth decade, degenerative changes were noted in the periphery of the inferior quadrant, including atrophy of the retinal pigment epithelium and bone-spicule pigmentations. On optical coherence tomography (OCT), changes at the inner-segment ellipsoid zone were seen, suggesting the loss of junctions between inner and outer segments. ERG at 55 years of age showed absent cone and significantly reduced rod responses; thus, the diagnosis changed from isolated cone dysfunction to progressive cone-rod disease.

Durlu et al. (2014) reported a consanguineous Turkish family in which 4 individuals had decreased central vision, extreme photophobia, and dyschromatopsia. None of the patients was blind at birth, but all experienced subsequent progressive vision loss. In all patients, a disrupted inner/outer segment line and the external limiting membrane were seen as a single blurry line at the central fovea, and the cone outer-segment tip line was absent. In the midperiphery, the rod inner/outer segment line was disrupted and blurry, and the rod outer-segment tip line (Verhoeff membrane) was absent. ERG revealed nonrecordable cone responses in all patients, whereas rod responses were nonrecordable in the oldest patient and subnormal in the other 3 patients. On electrooculography, the Arden ratio was abnormal in the youngest patient and flat in the others.

Using genome scan data from 10 members of a consanguineous Turkish family segregating autosomal recessive CORD, Durlu et al. (2014) performed linkage analysis and obtained a lod score of 3.92 at an approximately 1.14-Mb shared region on chromosome 12q21.33, flanked by markers rs12311684 and rs934891. Haplotype analysis around the locus revealed a second region of shared homozygosity in the patients, with a maximum length of 784,517 bp and a lod score of 3.40, delineated by rs2408366 and rs2130402 and located 621,093 bp telomeric to the larger region.

In a Turkish family in which 3 sibs had COD or CORD, Roosing et al. (2014) performed exome sequencing and identified a homozygous missense mutation in the POC1B gene (R106P; 614784.0001) that segregated with disease in the family and was not found in 189 ethnically matched controls or in the Exome Variant Server database. Exome sequencing in a Dutch man with CORD revealed compound heterozygosity for an in-frame 3-bp deletion and a splice site mutation in POC1B (614784.0002; 614784.0003); his unaffected parents were each heterozygous for 1 of the mutations, neither of which was found in 149 ethnically matched controls or in the NHLBI EVS database. Genomewide SNP homozygosity mapping of more than 400 unrelated individuals with autosomal recessive CORD, Leber congenital amaurosis (see 204000), or retinitis pigmentosa (see 268000) identified 8 probands with a large homozygous region spanning POC1B; however, Sanger sequencing of POC1B in those probands did not reveal additional pathogenic mutations. Subsequent Sanger sequencing of POC1B in a more specific cohort, including 21 patients diagnosed with ACHM, 110 with COD, and 112 with CORD, failed to reveal additional patients with POC1B mutations.

In a consanguineous Turkish family segregating autosomal recessive CORD mapping to chromosome 12q21.33, Durlu et al. (2014) sequenced 6 protein-coding candidate genes and independently identified homozygosity for the R106P missense mutation in the POC1B gene that was identified by Roosing et al. (2014) in an unrelated Turkish family. The mutation segregated with disease in the family and was not found in 113 population controls. Durlu et al. (2014) also identified a homozygous deletion at the disease locus, flanked by markers rs11105501 and rs10777224 and involving between 3,280 and 5,888 bp, that was present only in the affected family members. The sequences in the deleted region did not contain part of a gene, and there was no evidence indicative of a gene regulatory function. Durlu et al. (2014) therefore concluded that the deletion most likely did not underlie the disease.