Abstract

Retinal degenerations exemplify the genome-wide heterogeneity and challenges we face in assessment of variants of unknown significance. Challenging aspects of interpreting exome and genome variants as potentially pathogenic have unexpectedly revealed aberrant splicing as a common mechanism of disease, and here I will describe deep intronic mutations leading to the introduction of cryptic exons and the discovery of rare haplotypes of the L and M opsin genes, as a significant cause of disease. The ability to reprogramme human cells into induced pluripotent stem cells (iPSC) and then differentiate them into a wide range of different cell types has revolutionised our ability to study human disease. I will discuss how we can use iPSC derived from retinal degeneration patients to study the mechanisms of disease and to test potential therapies. Differentiating iPSC to retinal pigment epithelium (RPE) and optic cups can reveal potential mechanisms for retinal specificity, revealing why retinal cells are more susceptible to disease than other cells that express the same mutated genes. Furthermore, iPSC derived retinal cells are ideal for testing gene and mutation specific therapies.