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.

Progressive Keratoconus in a Patient With Severe Pectus Excavatum and a Cartilage Oligomeric Matrix Protein Gene Mutation: A Case Report

“…11 However, recent evidence questions the role of RIMS1 gene in the pathogenesis of cone–rod dystrophy type 7 and other retinal disorders. 30 In the case of our patient, no abnormal alterations in the rode–cone system were found on electrophysiological examination, making a diagnosis of cone–rod dystrophy type 7 unlikely.…”

Enhanced Learning and Memory in Patients with CRB1 Retinopathy

“…However, their scores in memory and executive function tests were variable, with some scores below average. The enhancement of some cognitive domains was attributed to genetic mutation rather than impaired visual function [ 19 , 20 ]. A kindred of four with the same PROM1 c.1117C > T p.Arg373Cys variant displayed superior memory recall.…”

“…Using an established paradigm to study cognitive function, one study reported a family with autosomal dominant cone-rod dystrophy and enhanced cognitive ability, who harboured a heterozygous missense variant (c.2459G > A, p.Arg820His) in RIMS1 , a gene known to be expressed in the ventricular zone, thalami, and hippocampus areas of the brain [ 19 ]. However, they subsequently reported co-inheritance of a heterozygous missense variant (c.1118C > T, p.Arg373Cys) in PROM1 [ 20 ], which is a gene known to be putative in adult hippocampal neurogenesis [ 21 ]. It is not known which gene/variant, or if both, may be associated with their augmented cognition.…”

No strong evidence to date for an association between RIMS1 and retinal dystrophy

“…RIMS1 has been previously associated with cone-rod dystrophy 7 (CORD7), and it is that association, reported in a four-generation non-consanguineous family [2], that has prompted the authors, and others, to take particular notice of variants in this gene in the context of retinal disease. We have very recently published our reassessment of the original family in whom RIMS1-associated disease was reported: the autosomal dominant cone-rod dystrophy is in fact attributable to a well-characterised pathogenic variant in the PROM1 gene (c.1118C>T, p.Arg373Cys) [3]. The phenotypes (ranging from macular, to cone-, or cone-rod, dystrophy) in the affected family members were in keeping with those reported for the PROM1 variant, and one member of that family was found to be affected despite not harbouring the RIMS1 variant.…”