Purpose To characterise the phenotype observed in a case series with macular disease and determine the cause. Design Multi-centre case series. Participants Six families (seven patients) with sporadic or multiplex macular disease with onset at 36-78 years, and one patient with age-related macular degeneration. Methods Patients underwent ophthalmic examination, exome, genome or targeted sequencing, and/or PCR amplification of the breakpoint followed by cloning and Sanger sequencing or direct Sanger sequencing. Main Outcome Measures Clinical phenotypes, genomic findings and a hypothesis explaining the mechanism underlying disease in these patients. Results All eight cases carried the same deletion encompassing the genes TPRX1, CRX and SULT2A1, which was absent from 382 control individuals screened by breakpoint PCR and 13,096 Clinical Genetics patients with a range of other inherited conditions screened by array comparative genomic hybridisation. Microsatellite genotypes showed that these seven families are not closely related, but genotypes immediately adjacent to the deletion breakpoints suggest they may share a distant common ancestor. Conclusions Previous studies had found that carriers for a single defective CRX allele that was predicted to produce no functional CRX protein had a normal ocular phenotype. Here we show that CRX whole-gene deletion in fact does cause a dominant late-onset macular disease.
