Importance: The families evaluated in this study represent the second report of cone-rod dystrophy (CRD) cases caused by mutations in RAB28, a recently discovered gene associated with CRD.
Objective: To determine the disease-causing gene in 2 families of Spanish descent presenting with CRD who do not have ABCA4 mutations.
Design, setting, and participants: Molecular genetics and observational case studies of 2 families, each with 1 affected proband with CRD and 3 or 5 unaffected family members. The affected individual from each family received a complete ophthalmic examination including assessment of refractive errors and best-corrected visual acuity, biomicroscopy, color fundus photography, electroretinography analysis, and visual-evoked potential analysis. After complete sequencing of the ABCA4 gene with negative results, the screening for disease-causing mutations was performed by whole-exome sequencing. Possible disease-associated variants were determined by filtering based on minor allele frequency, predicted pathogenicity, and segregation analysis in all family members.
Main outcomes and measures: The appearance of the macula was evaluated by clinical examination, fundus photography, and fundus autofluorescence imaging, and visual function was assessed by electroretinography. Disease-causing mutations were assessed by sequence analyses.
Results: Ophthalmologic findings included markedly reduced visual acuity, bull's eye maculopathy, foveal hyperpigmentation, peripapillary atrophy, dyschromatopsia, extinguished photopic responses, and reduced scotopic responses observed on electroretinography consistent with the CRD phenotype often associated with ABCA4 mutations. Although no ABCA4 mutations were detected in either patient, whole-exome sequencing analysis identified 2 new homozygous mutations in the recently described RAB28 gene, the c.172 + 1G>C splice site variant in IVS2 and the missense c.T651G:p.C217W substitution. Both variants were determined as deleterious by predictive programs and were segregated with the disease in both families. Sequencing of 107 additional patients of Spanish descent with CRD did not reveal other cases with RAB28 mutations.
Conclusions and relevance: Deleterious mutations in RAB28 result in a classic CRD phenotype and are an infrequent cause of CRD in the Spanish population.