Genome Analysis for Inherited Retinal Disease: The State of the Art

Abstract

Inherited retinal disease (IRD) is a major global cause of blindness caused by mutations in a wide spectrum of genes essential to the retinal structure, maintenance and function. Current clinical diagnostic strategies in the UK are focused on targeted gene panel testing either by enrichment or virtually. Whole exome and genome sequencing (WES and WGS) have been used in rare disease genetic discovery now for a decade and are being integrated into many research pipelines and diagnostic strategies exemplified by the Genomics England 100,000 genomes project.Here, we describe the current approaches to genetic and genomic analysis in IRD, the shortfalls and advantages of gene panel testing, WES and WGS in the context of single nucleotide, structural and copy number variants in coding, non-coding and intractable genomic regions.Looking ahead, the missing heritability in IRD may be consequent on a number of factors: new genes, ignored or undetectable variants, new diseases for known genes, etc. Improved detection of genomic variation afforded by WGS paired with expanded variant databases, advances in variant interpretation, developing our understanding of the effect of non-coding variation using multiomics and integrating deep phenotyping and genomic data into machine learning tools will be the driving forces in better diagnosis of rare disease and discovery of novel causes of disease in the post-genomic era.