Cone-Rod Dystrophy 9
A number sign (#) is used with this entry because of evidence that cone-rod dystrophy-9 (CORD9) is caused by homozygous or compound heterozygous mutation in the ADAM9 gene (602713) on chromosome 8p11.
For a general phenotypic description and a discussion of genetic heterogeneity of cone-rod dystrophy, see 120970.
Clinical FeaturesDanciger et al. (2001) described a consanguineous Brazilian family segregating autosomal recessive CORD. Affected family members had childhood-onset visual acuity impairment, which progressed over decades to major loss of central and then peripheral visual function. In the 2 adult family members tested, visual acuity was 20/200 with a preserved midperipheral crescent on visual field testing. Refractive error was modest myopia with astigmatism. Small posterior subcapsular cataracts were present.
Parry et al. (2009) studied 3 additional consanguineous families segregating CORD9. One was of Pakistani origin, 1 Tunisian Jewish, and the other Arab Muslim. Affected individuals in these families reported poor visual acuity in the first decade of life, but nystagmus and photophobia were not noted. Outer retinal atrophy was observed in the macula. Most patients had discrete white patches in the posterior pole and around the optic disc with a pigmentary retinopathy, anterior to the equator. The midperipheral retina showed minimal changes on clinical exam of young patients, and older patients peripheral pigmentary changes could be observed in some cases. Electroretinograms (ERGs) showed a similar degree of rod and cone involvement.
El-Haig et al. (2014) described a consanguineous Egyptian family in which a mother and 2 of her children had cone-rod dystrophy characterized by childhood-onset visual loss, reorganization of the retinal pigment epithelium with midperipheral grayish-white discoloration, attenuated retinal vasculature, and optic disc pallor. The mother also had bilateral anterior polar and posterior subcapsular cataracts and 1 of the children had a coloboma-like macular lesion. Bilateral dot cataract was diagnosed in 3 of her other 4 children, who did not have CORD, 1 of whom also had glaucoma.
MappingBy 4-point linkage analysis in the large Brazilian family segregating autosomal recessive CORD, Danciger et al. (2001) obtained a maximum lod score of approximately 7.6 at both D8S1769 and GATA101H09. Recombination events defined a critical interval of 8.7 cM between D8S1820 and D8S532. The 8p11 locus, designated CORD9, was immediately distal to but distinct from the RP1 gene (603937).
Parry et al. (2009) refined the CORD9 locus to a 2.95-Mb homozygous segment between SNPs rs10955025 and rs725401 containing 34 genes.
Molecular GeneticsIn 4 consanguineous families with cone-rod dystrophy linked to the CORD9 locus, including the family reported by Danciger et al. (2001), Parry et al. (2009) identified 4 different mutations in the ADAM9 gene (602713.0001-602713.0004).
In a consanguineous Egyptian family with autosomal recessive cone-rod dystrophy, El-Haig et al. (2014) identified a splice site mutation in intron 13 of the ADAM9 gene (602713.0005); the mother and 2 children were homozygous for the mutation, while the unaffected father and 4 unaffected children were heterozygous.
Exclusion Studies
In a Brazilian family segregating CORD9, Danciger et al. (2001) screened the exons of a dual specificity phosphatase gene (DUSP4; 602747), which maps in the CORD9 region, but identified no disease-causing mutations.