ClinVar

Ophthalmologic and molecular genetic studies were performed by Cremers et al. (1998) in a consanguineous family with individuals showing either retinitis pigmentosa (RP19; 601718) or cone-rod dystrophy (CORD3; 604116). Assuming pseudodominant (recessive) inheritance of allelic defects, linkage analysis positioned the causal gene at 1p21-p13 (lod score = 4.22), a genomic segment that harbors the ABCA4 gene involved in Stargardt disease and age-related macular degeneration. In 4 RP patients in this family they found homozygosity for a 5-prime splice site mutation, IVS30+1G-T. The 5 patients with CORD in this family were compound heterozygotes for the IVS30+1G-T mutation and a 5-prime splice site mutation in intron 40: IVS40+5G-A (601691.0010). Both splice site mutations were found heterozygously in 2 unrelated STGD patients (in whom the second mutation was either a missense mutation or unknown), but not in 100 control individuals. Since no Stargardt patient had been reported to carry 2 ABCR null alleles and the RP phenotype was more severe than the STGD phenotype, Cremers et al. (1998) hypothesized that the intron 30 splice site mutation represented a true null allele. Since the intron 30 mutation was found heterozygously in the CORD patients, the intron 40 mutation probably rendered the exon 40 5-prime splice site partially functional. These results showed that mutations in the ABCR gene result not only in STGD and ARMD, but also in autosomal recessive RP and CORD.