Copy Number Variation Is An Important Contributor to the Genetic Causality of Inherited Retinal Degenerations

PURPOSE: Despite substantial progress in sequencing, current strategies can genetically solve only about 55–60% of inherited retinal degeneration (IRD) cases. This can partially be attributed to elusive mutations in the known IRD genes, which are not easily identified by the targeted next-generation sequencing (NGS) or Sanger sequencing approaches. We hypothesized that copy number variations (CNVs) are a major contributor to the elusive genetic causality of IRDs. METHODS: Twenty-eight patients, previously unsolved with a targeted NGS, were investigated with whole-genome SNP and CGH arrays. RESULTS: Deletions in the IRD genes were detected in five of twenty-eight families, including a de novo deletion. We suggest that the de novo deletion occurred through non-allelic homologous recombination (NAHR) and we constructed a genomic map of NAHR-prone regions with overlapping IRD genes. In this study we also report an unusual case of recessive retinitis pigmentosa due to compound heterozygous mutations in SNRNP200, a gene that is typically associated with the dominant form of this disease. CONCLUSIONS: CNV mapping substantially increased the genetic diagnostic rate of IRDs, detecting genetic causality in 18% of previously unsolved cases. Extending the search to other structural variations (SVs) will likely demonstrate an even higher contribution to genetic causality of IRDs.