Genetic and Phenotypic Characterization of a Large Cohort of Patients with BBS1-Retinopathy

To analyze the clinical spectrum and natural history of patients with BBS1-associated retinopathy.

A single-center retrospective, observational cohort study.

Molecularly confirmed patients with bi-allelic disease-causing variants in BBS1.

Clinical data were extracted from physical and electronic records. Retinal imaging and electrophysiology were analyzed cross-sectionally and longitudinally. Genetic results were reviewed, and the variants assessed.

Molecular genetic testing and clinical findings, including best-corrected visual acuity (BCVA), qualitative and quantitative analyses of retinal imaging, and electrophysiology.

Forty-eight patients were identified and assessed longitudinally; 20.8% had isolated retinopathy. The mean age at baseline visit was 28.7 ± 13.7 years, and the mean follow-up was 10.6 ± 7.7 years. The median BCVA was 0.47 logarithm of minimum angle of resolution (LogMAR) (interquartile range 0.3-0.8) at baseline and 1.3 LogMAR (interquartile range 0.7-2.4) at follow-up, with an average decline of 0.05 LogMAR/year. Obesity and polydactyly were the most frequent systemic associations within our cohort. The mean central macular thickness (CMT) at baseline and follow-up was 179.7 ± 43.1 μm and 166.6 ± 50.3 μm. The mean outer nuclear layer thickness (ONLT) at baseline and follow-up was 32.6 ± 21.5 μm and 25.6 ± 22.1 μm. The rate of decline for CMT and ONLT was 4.2 μm and 1.7 μm per year, respectively. When the different genotypes were compared, there was no statistically significant difference between the rates of progression. However, homozygous patients for the most common variant p.(Met390Arg) had an older age of onset and reached legal blindness at an older age compared with the other genotypes. Of the patients who had electrophysiology available, 19 of 27 had rod-cone pattern dysfunction, (6/27) a similar degree of rod and cone dysfunction. One had a cone-rod dystrophy pattern, and the other had only macular dysfunction; both developed a rod-cone pattern during follow-up. Seven BBS1 variants were reported, and characteristic genotype-phenotype correlations were revealed.

This study is a large cohort with long longitudinal follow-up of molecularly confirmed patients with BBS1-associated retinopathy. The ocular and systemic phenotype, detailed imaging, electrophysiological features, and disease progression are described, expanding the spectrum of functional and structural phenotypes related to BBS1 variants.

Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.