Dominant Cone Rod Dystrophy, Previously Assigned to a Missense Variant in RIMS1, Is Fully Explained by Co-Inheritance of a Dominant Allele of PROM1

Abstract

Purpose: Autosomal dominant cone rod dystrophy 7 (CORD7) was initially linked to the gene RIMS1 and reported in a 4-generation British family in 1998. The purpose of this study was to investigate the legitimacy of this association, and to correctly characterize the genetic cause of this condition.

Methods: The allele frequency of RIMS1 c.2459G>A, p.Arg820His, was investigated in the Genomes Aggregation Dataset (gnomAD) datasets and whole genome sequencing (WGS) was performed for 4 members of the CORD7 family with filtering of rare pathogenic variants in a virtual gene panel comprising all genes known to be associated with inherited retinal dystrophy (IRD). Cytogenetic analysis was performed to rule out interchromosomal translocation.

Results: RIMS1 p.Arg820His has a maximal carrier frequency of >1:5000 in Europeans. A previously well-characterized PROM1 variant: c.1118C>T, p.Arg373Cys, was detected in 9 affected members of the CORD7 family who underwent WGS or direct sequencing. One affected family member is now known to have macular dystrophy in the absence of RIMS1 p.Arg820His. Clinical analysis of affected family members and 27 individuals with retinopathy associated with the same - PROM1 - variant showed consistent phenotypes.

Conclusions: The case for pathogenicity of RIMS1 p.Arg820His is not strong based on its presence on 10 alleles in the gnomAD dataset and absence from additional CORD affected individuals. The finding of a known pathogenic variant in PROM1 correlates well with the phenotypic characteristics of the affected individuals, and is likely to account for the condition. Clear evidence of association between RIMS1 and a retinal dystrophy is yet to be described.

Figure 1.

Four-generation pedigree of the British CORD7 family. Family members affected with autosomal dominant CRD are shaded. Individuals known to harbour the RIMS1 variant p.Arg820His are labelled as “M1+”, and those found to carry the PROM1 variant p.Arg373Cys, as “M2+”. One affected individual (IV:9) has a clinical diagnosis of macular dystrophy in the absence of the RIMS1 variant.

Figure 2.

Fundoscopic features of 3 affected members of the family originally diagnosed with CORD7 (left column). Retinal changes among the affected individuals included mild maculopathy retinal pigment epithelium (RPE) changes, extensive macular and peripheral atrophy, peripheral pigmentation, bull's eye maculopathy and attenuation of retinal vessels. Note the significant intrafamilial phenotypic variability within these three images. Adjacent to each of the images, are 3 known cases of PROM1 macular dystrophy, unrelated to the CORD family (right column). Note the similar clinical appearance with the cases shown on the left.