Cone-Rod Dystrophy 2

A number sign (#) is used with this entry because of evidence that cone-rod dystrophy-2 (CORD2) is caused by heterozygous mutation in the CRX gene (602225) on chromosome 19q13.

Cone-rod dystrophy (CORD) characteristically leads to early impairment of vision. An initial loss of color vision and of visual acuity is followed by nyctalopia (night blindness) and loss of peripheral visual fields. In extreme cases, these progressive symptoms are accompanied by widespread, advancing retinal pigmentation and chorioretinal atrophy of the central and peripheral retina (Moore, 1992). In many families, perhaps a majority, central and peripheral chorioretinal atrophy is not found (Tzekov, 1998).

Genetic Heterogeneity of Autosomal Cone-Rod Dystrophy

There are several other autosomal forms of CORD for which the molecular basis is known. CORD3 (604116) is caused by mutation in the ABCA4 gene (601691) on chromosome 1p22. CORD5 (600977) is caused by mutation in the PITPNM3 gene (608921) on chromosome 17p13. CORD6 (601777) is caused by mutation in the GUCY2D gene (600179) on chromosome 17p13.1. CORD7 (603649) is caused by mutation in the RIMS1 gene (606629) on chromosome 6q13. CORD9 (612775) is caused by mutation in the ADAM9 gene (602713) on chromosome 8p11. CORD10 (610283) is caused by mutation in the SEMA4A gene (607292) on chromosome 1q22. CORD11 (610381) is caused by mutation in the RAXL1 gene (610362) on chromosome 19p13. CORD12 (612657) is caused by mutation in the PROM1 gene (604365) on chromosome 4p15. CORD13 (608194) is caused by mutation in the RPGRIP1 gene (605446) on chromosome 14q11. CORD14 (see 602093) is caused by mutation in the GUCA1A gene (600364) on chromosome 6p21. CORD15 (613660) is caused by mutation in the CDHR1 gene (609502) on chromosome 10q23. CORD16 (614500) is caused by mutation in the C8ORF37 gene (614477) on chromosome 8q22. CORD18 (615374) is caused by mutation in the RAB28 gene (612994) on chromosome 4p15. CORD19 (615860) is caused by mutation in the TTLL5 gene (612268) on chromosome 14q24. CORD20 (615973) is caused by mutation in the POC1B gene (614784) on chromosome 12q21. CORD21 (616502) is caused by mutation in the DRAM2 gene (613360) on chromosome 1p13.

A diagnosis of CORD was made in an individual with a mutation in the AIPL1 gene (604392.0004) on chromosome 17p13.1, as well as in an individual with a mutation in the UNC119 gene (604011.0001) on chromosome 17q11.2.

Other mapped loci for autosomal CORD include CORD1 (600624) on chromosome 18q21.1-q21.3; CORD8 (605549) on chromosome 1q12-q24; and CORD17 (615163) on chromosome 10q26.

For a discussion of X-linked forms of cone-rod dystrophy, see CORDX1 (304020).

Hittner et al. (1975) described an extensively affected kindred with an autosomal dominant dystrophy of the retinal photoreceptors and pigment epithelium that is characterized by simultaneous abiotrophic degeneration of rods and cones. The onset of decreased central vision with concurrent progressive constriction of peripheral visual fields occurs prior to age 10. Unlike previously described cone dystrophies, there is an inexorable progression to no light perception. Ferrell et al. (1981) provided follow-up on the family reported by Hittner et al. (1975). In all, 25 affected persons had been identified.

Evans et al. (1995) reported the clinical features of 34 affected members in 4 generations. Loss of visual acuity occurred in the first decade of life, onset of night blindness occurred after 20 years of age, and little visual function remained after the age of 50 years. Central and, later, peripheral retinal fundus changes were associated with central scotoma, pseudoaltitudinal field defects, and finally, global loss of function. Psychophysical and electrophysiologic testing before the age of 26 years showed more marked loss of cone than of rod function. Evans et al. (1995) found complete blindness (no light perception) in only 3 of the 34 patients studied, and these 3 were all over 65 years of age. Serious effects on visual acuity (light perception only) were present in 10 other patients; however, their mean age was 60.3 years. All other patients retained some visual acuity.

Papaioannou et al. (1998) reported a 4-generation family of Greek origin with clinical features similar to those described in the British family by Evans et al. (1994).

Itabashi et al. (2004) characterized the clinical features of a Japanese family with CORD. The ophthalmic findings included CORD with negative-type electroretinograms (ERGs) and a rapid progression after age 40 years. The authors concluded that genotype-phenotype correlation in the CRX gene in their patient and others reported in the literature suggested that the negative-type ERG might be indicative of a mutation in the CRX gene.

In the large kindred with autosomal dominant cone-rod dystrophy studied by Evans et al. (1994), it appeared that inheritance was influenced by meiotic drive, resulting in segregation distortion. Affected fathers (N = 25) produced 71 children of whom 31 (44%) were affected, a value approximating the expected 1:1 ratio; however, 63 of 101 children (63%) born to 26 affected mothers inherited the CORD gene. The cumulative binomial distribution calculation for this finding in the progeny of affected mothers gave p = 0.008.

In a large British family segregating cone-rod dystrophy, Evans et al. (1994) found linkage of the disorder to chromosome 19q13.1-q32.1 (maximum lod of 10.08 distal to D19S47). In a family reported by Papaioannou et al. (1998) who had clinical features similar to those described in the British family by Evans et al. (1994), linkage analysis gave a maximum lod score of 2.7 at theta = 0.0 with marker D19S412.

Additional Heterogeneity

Kylstra and Aylsworth (1993) reported a case of cone-rod retinal dystrophy in association with neurofibromatosis type I (NF1; 162200) and suggested a localization for CORD (CORD4) close to the NF1 gene (613113) on 17q.

Exclusion Mapping

In the family originally reported by Hittner et al. (1975), Ferrell et al. (1981) found no linkage with 17 marker loci. Specifically, a large negative lod score with Rh argued against location of the CORD gene on 1p, a large negative lod score with acid phosphatase-1 argued against its location on 2p, and a large negative lod score with ABO and transcobalamin II argued against its location on 9q.

In affected members of 2 pedigrees with CORD2, Freund et al. (1997) identified a missense and a frameshift mutation in the CRX gene, an OTX-like homeobox gene. The authors showed that the missense mutation (602225.0001) was not a polymorphic variant and concluded that mutation in the CRX gene is responsible for the CORD2 phenotype.

In a Japanese family with CORD, Itabashi et al. (2004) found a 1-bp deletion in exon 1 of the CRX gene (602225.0009).

By whole-exome sequencing in a group of 50 patients with CORD who were negative for mutations in known retinal disease genes, Dharmat et al. (2017) identified compound heterozygosity for a nonsense mutation (R405X) and a missense mutation (L614P) in the IFT81 gene (605489) in a 22-year-old woman. Her unaffected parents were each heterozygous for 1 of the mutations, neither of which was found in internal controls or public variant databases. The L614P variant was not able to rescue ciliogenesis defects in IFT81 -/- hTERT-RPE1 cells or zebrafish. The proband had progressively decreasing vision with photophobia from age 12 years, and examination revealed impaired color vision and decreased visual acuity, characteristic pigmented lesions in the fundus, reduced responses on ERG that were more severe in cones than in rods, and thinning of the retinal layers in the macular area on ocular coherence tomography. She had no extraocular anomalies. The authors concluded that IFT81 was a candidate gene for inherited nonsyndromic retinal dystrophy.