Chapter 6 - Genetic architecture of inherited retinal disease

Abstract

Inherited retinal disease (IRD), are a group of rare, clinically heterogeneous diseases that are the major cause of registered blindness among working adults. IRDs as a group are the most genetically diverse inherited conditions with >260 causal genes described so far. The genetic architecture is further complicated by the variable expressivity and diverse mutation profile of the IRD genes, ranging from single nucleotide, truncating and frameshift variants to the more recently highlighted copy number, regulatory, and splice-site variants. This genetic heterogeneity stems from an equally diverse set of disease mechanisms with underlying vulnerabilities in nearly every aspect of photoreceptor physiology and biochemistry. This chapter describes the current understanding of the genetic architecture of IRDs, highlighting the pathways affected in photoreceptor degeneration, the underlying genetic etiology and diverse spectrum of alleles observed in IRD.