Late-onset pattern macular dystrophy mimicking ABCA4 and PRPH2 disease is caused by a homozygous frameshift mutation in ROM1

• Published in: Cold Spring Harbor molecular case studies 2019-06, Vol.5 (3), p.a003624
• Main Authors: Ma, Chu Jian, Lee, Winston, Stong, Nicholas, Zernant, Jana, Chang, Stanley, Goldstein, David, Nagasaki, Takayuki, Allikmets, Rando
• Format: Article
• Language: English
• Subjects: Acuity; Amino acids; ATP-Binding Cassette Transporters - genetics; Chromosome 11; Chromosomes; Dystrophy; Electroretinography; Eye Proteins - genetics; Female; Frameshift Mutation; Gene deletion; Homozygote; Humans; Integral membrane proteins; Macular Degeneration - diagnostic imaging; Macular Degeneration - genetics; Macular Degeneration - pathology; Middle Aged; Mimicry; Mutation; Peripherins - genetics; Phenotype; Phenotypes; Photoreceptors; Proteins; Rapid Communication; Retina; Retina - diagnostic imaging; Retina - pathology; Tetraspanins - genetics; Visual acuity; Whole Exome Sequencing
• ISSN: 2373-2865; 2373-2873
• DOI: 10.1101/mcs.a003624

ROM1 (retinal outer segment membrane protein 1) is a 351-amino acid integral membrane protein on Chromosome 11q, with high structural similarity to PRPH2/RDS. Localized at the rims of photoreceptor outer segments (OSs), it is required for the maintenance of OS structure. Here, we describe a case with a phenotypic manifestation of a homozygous single-base pair deletion, c.712delC (p.Leu238Cysfs*78) in the gene, resulting in early termination at exon 2. The variant was detected by whole-exome sequencing (WES) in a 63-yr-old Caucasian woman with late-onset pattern macular dystrophy. Notably, although the phenotype resembles those caused by pathogenic variants in or , no pathogenic variants in these, or any other plausible candidate genes, were identified by WES. Clinical features include the presence of hyperautofluorescent flecks, relative sparing of the central macula, and preserved visual acuity. Reduced visual sensitivity was detected among flecked regions in the retina; however, full-field electroretinogram testing revealed no generalized cone dysfunction. The described first case of the complete loss of ROM1 protein function in the retina suggests its sufficiency for late-onset macular dystrophy. and pattern macular dystrophies exhibit phenotype overlap, which may be attributable to their shared role in maintenance of the photoreceptor outer segment structure.