Long-read sequencing and next-generation CRISPR editors: a unified pipeline for rare disease precision medicine with ethical and regulatory perspectives

Abstract

Rare diseases, most of which have a genetic basis, remain a major challenge due to diagnostic delays and limited therapeutic options, particularly within the Middle Eastern regions. These countries exhibit a heightened prevalence of genetic disorders attributable to their distinctive genetic architecture. Advances in long-read sequencing (LRS) technologies have significantly improved our ability to detect complex genetic variations, including structural variants (SVs), repeat expansions, and mutations in previously inaccessible genomic regions, thereby increasing the diagnostic yield in rare disease cohorts. In parallel, the rapid evolution of gene-editing platforms such as CRISPR/Cas9, base editors, and prime editors has opened new possibilities for addressing the biological pathways of the disease and achieving precise therapeutic correction of pathogenic variants causing the disease. Importantly, the integration of LRS with gene-editing approaches establishes a continuum from accurate variant discovery and functional characterization to the development of personalized therapies. This review highlights recent progress in both fields, discusses their complementary roles in rare disease research, and explores the translational opportunities and ethical challenges of combining these technologies to advance precision medicine. In addition, the review addresses emerging ethical and regulatory considerations associated with the clinical translation of long-read sequencing and next-generation gene-editing technologies, particularly in the context of rare disease precision medicine.