Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, North Carolina, USA; email:
Annu Rev Med. 2023 Jan 27;74:489-502. doi: 10.1146/annurev-med-042921-110721.
Exome sequencing (ES) and genome sequencing (GS) have radically transformed the diagnostic approach to undiagnosed rare/ultrarare Mendelian diseases. Next-generation sequencing (NGS), the technology integral for ES, GS, and most large (100+) gene panels, has enabled previously unimaginable diagnoses, changes in medical management, new treatments, and accurate reproductive risk assessments for patients, as well as new disease gene discoveries. Yet, challenges remain, as most individuals remain undiagnosed with current NGS. Improved NGS technology has resulted in long-read sequencing, which may resolve diagnoses in some patients who do not obtain a diagnosis with current short-read ES and GS, but its effectiveness is unclear, and it is expensive. Other challenges that persist include the resolution of variants of uncertain significance, the urgent need for patients with ultrarare disorders to have access to therapeutics, the need for equity in patient access to NGS-based testing, and the study of ethical concerns. However, the outlook for undiagnosed disease resolution is bright, due to continual advancements in the field.
外显子组测序（ES）和全基因组测序（GS）从根本上改变了对未确诊的罕见/超罕见孟德尔疾病的诊断方法。下一代测序（NGS）是 ES、GS 和大多数大型（100 个以上基因）基因面板的关键技术，它为患者带来了以前难以想象的诊断、医疗管理的改变、新的治疗方法以及准确的生殖风险评估，同时也发现了新的疾病基因。然而，挑战依然存在，因为目前大多数个体仍无法通过 NGS 进行诊断。改进的 NGS 技术已经产生了长读测序，这可能会解决一些通过当前短读 ES 和 GS 无法诊断的患者的诊断问题，但它的有效性尚不清楚，而且费用昂贵。其他持续存在的挑战包括不确定意义的变异的解决、超罕见疾病患者急需获得治疗方法、患者获得基于 NGS 的检测的公平性以及对伦理问题的研究。然而，由于该领域的不断进步，未确诊疾病的解决前景一片光明。
