Clinical applications of high-throughput genetic diagnosis in inherited retinal dystrophies: Present challenges and future directions

Abstract

The advent of next generation sequencing (NGS) techniques has greatly simplified the molecular diagnosis and gene identification in very rare and highly heterogeneous Mendelian disorders. Over the last two years, these approaches, especially whole exome sequencing (WES), alone or combined with homozygosity mapping and linkage analysis, have proved to be successful in the identification of more than 25 new causative retinal dystrophy genes. NGS-approaches have also identified a wealth of new mutations in previously reported genes and have provided more comprehensive information concerning the landscape of genotype-phenotype correlations and the genetic complexity/diversity of human control populations. Although whole genome sequencing is far more informative than WES, the functional meaning of the genetic variants identified by the latter can be more easily interpreted, and final diagnosis of inherited retinal dystrophies is extremely successful, reaching 80%, particularly for recessive cases. Even considering the present limitations of WES, the reductions in costs and time, the continual technical improvements, the implementation of refined bioinformatic tools and the unbiased comprehensive genetic information it provides, make WES a very promising diagnostic tool for routine clinical and genetic diagnosis in the future.

Keywords: Next generation sequencing, Identification of novel causative genes, Inherited retinal dystrophies, Genetic diagnosis, Whole exome sequencing

Core tip: This review focuses on the application of next generation sequencing (NGS)-based methods [whole genome sequencing, whole exome sequencing (WES), targeted exome sequencing] for genetic diagnosis and novel gene identification in hereditary retinal dystrophies. Advances over the last two years concerning NGS accuracy, reliability, development of bioinformatics tools, together with the drop in costs and time required for the analysis have allowed thirty novel genes to be identified, plus a large number of new mutations in previously reported genes. NGS techniques (particularly WES) are revolutionizing genetic diagnosis and have clear applications in clinical practice, helping to pave the way for personalized medicine. Present challenges and future directions are also discussed.