Exploring The Genetic Basis of Rare Diseases Through Next-Generation Sequencing

Abstract

An establishment of Next-Generation Sequencing (NGS) as a powerful tool in elucidating the genetic complexity of rare diseases, providing tremendous throughput in the selection of known and/or novel pathogenic variant(s) with exceptional resolution. In this review, we describe the use of technologies such as Whole Exmore Sequencing (WES), Whole Genome Sequencing (WGS), and targeted sequencing in rare disease research by integration with animal models, namely mouse, zebra fish and dogs. They are these important physiological and genetic parallels to human biology that allow functional validation of mutations using gene editing tools like CRISPR-Cas9. To exemplify, while mice are the primary candidates for mutagenesis and studies of neurodevelopment diseases, zebra fish are highly suited for modeling congenital conditions because of transparency and rapid development, and canine models are the best in closely mimicking human neuromuscular diseases to facilitate translational studies. NGS makes possible the discovery of disease mechanisms and drug development; however, there are certain challenges associated with NGS that prevail like the ethical issues, species gene expression variability and poor genomic annotation in non-model species. Nevertheless, further NGS advances including integration with CRISPR-based functional validation, comparative genomics and translational research are taking the field further toward precision personalized medicine. The future directions seek to incorporate multi omics, expand genomic databases, and utilize artificial intelligence to improve variant interpretation and narrow the gap between discovery and clinical use of rare genetic disease treatment.