Association of Missense Variants in VSX2 With a Peculiar Form of Congenital Stationary Night Blindness Affecting All Bipolar Cells

Abstract

ImportanceCongenital stationary night blindness (CSNB) is an inherited stationary retinal disorder that is clinically and genetically heterogeneous. To date, the genetic association between some cases with CSNB and an unusual complex clinical picture is unclear.ObjectiveTo describe an unreported CSNB phenotype and the associated gene defect in 3 patients from 2 unrelated families.Design, Setting, and ParticipantsThis retrospective case series was conducted in 2021 and 2022 at a national referral center for rare ocular diseases. Data for 3 patients from a cohort of 140 genetically unsolved CSNB cases were analyzed clinically and genetically.ExposuresComplete ocular examination including full-field electroretinography and multimodal fundus imaging (spectral-domain optical coherence tomography, color, infrared reflectance, and short-wavelength autofluorescence photographs) were performed. The gene defect was identified by exome sequencing and confirmed by Sanger sequencing and co-segregation analysis in 1 family. Screening was performed for genetically unsolved CSNB cases for VSX2 variants by direct Sanger sequencing.Main Outcomes and MeasuresOcular and molecular biology findings.ResultsThe series included 3 patients whose clinical investigations occurred at ages in the early 30s, younger than 12 years, and in the mid 40s. They had nystagmus, low stable visual acuity, and myopia from birth and experienced night blindness. Two older patients had bilateral lens luxation and underwent lens extraction. Full-field electroretinography revealed an electronegative Schubert-Bornschein appearance, combining characteristics of incomplete and complete CSNB, affecting the function of rod and cone ON- and OFF-bipolar cells. Exome sequencing and co-segregation analysis in a consanguineous family with 2 affected members identified a homozygous variant in VSX2. Subsequently, screening of the CSNB cohort identified another unrelated patient harboring a distinct VSX2 variant.Conclusions and RelevanceThis case series revealed a peculiar pan-bipolar cell retinopathy with lens luxation associated with variants in VSX2. Clinicians should be aware of this association and VSX2 added to CSNB diagnostic gene panels.