Cone-Rod Dystrophy 21
A number sign (#) is used with this entry because of evidence that retinal dystrophy with early macular involvement (CORD21) is caused by homozygous or compound heterozygous mutation in the DRAM2 gene (613360) on chromosome 1p13.
For a general phenotypic description and discussion of genetic heterogeneity of cone-rod dystrophy (CORD), see 120970.Clinical Features
El-Asrag et al. (2015) studied a 5-generation consanguineous Pakistani family segregating autosomal recessive adult-onset retinal dystrophy with early macular involvement. Affected individuals described increasing difficulty with close visual tasks beginning in their thirties. There was progressive loss of visual acuity in all symptomatic individuals; light sensitivity and night blindness were inconsistent features of advanced disease. Funduscopy revealed maculopathy in all symptomatic individuals examined, with peripheral retinal degeneration being a frequent finding in older subjects. Optical coherence tomography in a presymptomatic individual suggested early central photoreceptor cell loss. El-Asrag et al. (2015) also studied a 47-year-old woman of European ancestry who experienced blurred vision at age 29 and was found to have maculopathy on funduscopy. At age 35, she developed night vision problems and sensitivity to light; examination revealed mild peripheral retinal degeneration in addition to the maculopathy. At age 47, she had visual acuity of 20/200 in each eye with severely attenuated or absent full-field and pattern electroretinograms, suggesting generalized rod-cone dysfunction.
Sergouniotis et al. (2015) examined 16 affected individuals, ranging in age from 19 to 56 years, from 6 families with DRMA2-retinopathy; 1 of the patients was presymptomatic. All 15 symptomatic patients had central visual loss unaccompanied by nyctalopia or light hypersensitivity. Eleven of the 15 developed symptoms in the third decade of life. A granular macular appearance, often associated with white/yellow dots, was an early funduscopic feature. There was an ill-defined ring on fundus autofluorescence (FAF) imaging. Optical coherence tomography (OCT) showed loss of the ellipsoid zone perifoveally in the 19-year-old presymptomatic individual. The central atrophic area enlarged over time and funduscopy showed peripheral degeneration in 7 of 9 individuals who were examined 10 or more years after becoming symptomatic; some of these patients developed nyctalopia and light hypersensitivity. Electrophysiology showed generalized retinal dysfunction in 3 of 5 individuals who were tested 10 or more years after becoming symptomatic.Inheritance
The transmission pattern of cone-rod dystrophy in the Pakistani family reported by El-Asrag et al. (2015) was consistent with autosomal recessive inheritance.Mapping
Using DNA from 7 affected members of a 5-generation consanguineous Pakistani family with adult-onset retinal dystrophy with early macular involvement, El-Asrag et al. (2015) performed homozygosity mapping and identified 2 homozygous regions shared among all 7 patients: a 10.1-Mb interval on chromosome 1 between SNPs rs6677953 and rs814987, and a 2.9-Mb region on chromosome 7. After identification of a 1-bp deletion in the DRAM2 gene on chromosome 1p13 that segregated with disease (see MOLECULAR GENETICS), a maximum 2-point lod score of 2.4 was obtained between the mutation and the disease in 9 genotyped family members.Molecular Genetics
Using DNA from 1 affected member of a 5-generation consanguineous Pakistani family segregating autosomal recessive adult-onset retinal dystrophy with early macular involvement, El-Asrag et al. (2015) performed whole-exome sequencing and identified homozygosity for a 1-bp deletion in the DRAM2 gene (613360.0001) on chromosome 1p13. Sanger sequencing confirmed segregation with disease in the family, and the mutation was not found in 159 ethnically matched controls, or in the dbSNP or Exome Variant Server databases; however, the 1-bp deletion was detected in heterozygous state in 1 of 61,486 unrelated individuals in the ExAC database. El-Asrag et al. (2015) analyzed the DRAM2 gene in 322 probands with various forms of retinal dystrophy, including 74 patients diagnosed with retinitis pigmentosa, 154 with cone-rod dystrophy or macular dystrophy, and 94 with infantile-onset retinal dystrophy, and identified a woman of European ancestry from the cone-rod/macular dystrophy panel who was compound heterozygous for a nonsense mutation (W165X; 613360.0002) and a missense mutation (S44N; 613360.0003) in DRAM2. Inspection of previously generated whole-exome sequencing data from unsolved cases of retinal dystrophy revealed a homozygous 3-bp deletion in DRAM2 (613360.0004) in an Indian woman who primarily exhibited maculopathy without generalized retinal dysfunction. In addition, a gene-based case-control association study was conducted using exome sequencing data from 18 probands with retinal disease and 1,917 controls, which revealed 2 more patients with DRAM2 mutations (see, e.g., 613360.0005). Both of these patients exhibited a notably similar ocular phenotype to that of the previously identified patients with DRAM2 mutations.