gms | German Medical Science

Most inherited retinal diseases (e.g. retinitis pigmentosa, Leber congenital amaurosis, cone/cone-rod dystrophies, congenital stationary night blindness) result from mutations in many genes which has long hampered comprehensive genetic analysis. However, pinpointing the disease-causing mutations is a prerequisite for personalized genetic counseling, specification of recurrence risks, prediction of the clinical course and will be essential for gene-specific therapies. With the advent of next-generation sequencing (NGS), allowing for rapid and cost-effective simultaneous analysis of the known disease genes, these genetically extremely heterogeneous disease groups have become accessible to comprehensive analysis, truly revolutionizing genetic diagnostics. The diagnostic yield has increased dramatically, and most patients can now be provided with a genetic diagnosis. Moreover, quantitative readout of high-coverage NGS data may identify disease-causing copy number variations that would escape mere sequence analysis. Another type of “hidden mutations” localizes in non-coding exons with regulatory roles for gene expression, and these largely unstudied gene regions should therefore be considered in NGS targeting retinal diseases genes. Simultaneous analysis of multiple genes can result in many candidate variants; however, single-gene testing in genetically heterogeneous conditions is error-prone, and sound interpretation requires consideration of the full variant load in all genes. For patients whose genetic basis of disease remains elusive even after NGS of a gene panel, whole-exome sequencing (targeting virtually all exons of all human genes) offers the opportunity to identify yet unknown retinal disease genes. Examples from our studies for the aforementioned scenarios will be demonstrated.