Novel RCBTB1 variants causing later-onset non-syndromic retinal dystrophy with macular chorioretinal atrophy

Abstract

Background: Variants in RCBTB1 were recently described to cause a retinal dystrophy with only eight families described to date and a predominant phenotype of macular atrophy and peripheral reticular degeneration. Here, we further evaluate the genotypic and phenotypic characteristics of biallelic RCBTB1-associated retinal dystrophy in a North American clinic population.

Methods: A retrospective analysis of genetic and clinical features was performed in individuals with biallelic variants in RCBTB1.

Results: Three unrelated individuals of French-Canadian descent with rare biallelic RCBTB1 variants were identified. All individuals shared a novel p.(Ser342Leu) missense variant; one patient was homozygous whereas the other two each possessed a second unique novel variant p.(Gln120*) and p.(Pro224Leu). All three had macula-predominant disease with symptom onset in the fifth decade of life.

Conclusion: This report adds to the genetic diversity of RCBTB1-associated disease. These cases confirm the later-onset, relative to many other retinal dystrophies, and macular focus of disease described in most cases to-date. They are thus a reminder of considering hereditary disease in the differential for later-onset macular atrophy.

Keywords: Macular atrophy; RCBTB1; retinal dystrophy.

Figure 1:. Location and features of disease-associated RCBTB1 variants

The schematic figure shows the location of all the disease-associated variants in RCBTB1 described in the literature and in this report. Novel variants are shown in bold font.

Figure 2:. Fundus imaging of patients with RCBTB1-associated retinal dystrophy

Fundus photography (A-C), fundus autofluorescence (FAF; D-F), and SD-OCT (G-I) were obtained in all patients. In Patient 1, nummular patches of fovea-abutting atrophy were observed on exam and with fundus photography (A). Subtle pigment mottling was present in the midperipheral retina. FAF (D) highlighted the nummular nature of the atrophy and also showed generalized macular hypofluorescence without prominent peripheral disruption. SD-OCT (G) delineated areas of atrophy with a restricted island of foveal sparing in addition to showing more widespread RPE irregularities. In Patient 2, fundus exam and photography (B) showed fovea-sparing macular atrophy. Fine pigment deposits, nummular areas of chorioretinal atrophy, and occasional larger pigment clumps were present in the peripheral retina. FAF (E) further illustrated the distribution of atrophy and pigment disruption. SD-OCT (H) showed generally intact foveal lamination. Areas of atrophy were also present with associated cystoid spaces and outer retinal tubulations (ORTs). In Patient 3, fundus exam and photography (G) showed extensive macular atrophy with several prominent pigment clumps. Fine pigmentary deposits in the peripheral retina formed a reticular pattern in areas. FAF (H) showed coalescing nummular hypofluorescence in the macula with narrow strips of preserved signal. Reduced hypofluorescence was present throughout the midperiphery. Extensive chorioretinal atrophy and ORTs were present on SD-OCT (I) with limited areas of preserved outer retinal structure.

Figure 3:. Evolution of macular findings in a single patient with RCBTB1-associated retinal dystrophy

Progressive macular disease was seen over a 3 year interval in Patient 1 as evaluated in near-infrared (A,B), fundus autofluorescence (C,D), and SD-OCT (E,F) imaging, presented for the right eye.