基因诊断的新技术彻底改变了对罕见疾病的理解和管理。这篇综述强调了先天性免疫错误(IEI)的遗传诊断的重大进展和最新进展,包括一组以免疫系统缺陷为特征的疾病,导致对感染的易感性增加,自身免疫,自身炎症性疾病,过敏,和恶性肿瘤。各种诊断方法,包括靶向基因测序面板,整个外显子组测序,全基因组测序,RNA测序,或者蛋白质组学,已经能够识别罕见疾病的致病遗传变异。这些技术不仅促进了IEI的准确诊断,而且为潜在的分子机制提供了有价值的见解。新兴技术,目前主要用于研究,比如光学基因组作图,在不久的将来,单细胞测序或人工智能的应用将为遗传性免疫缺陷的病因提供更多的见解。将基因诊断整合到临床实践中显著影响患者护理。基因检测可以实现早期诊断,促进及时干预和个性化治疗策略。此外,建立基因诊断对于遗传咨询和预后评估是必要的.鉴定与先天免疫错误相关的特定遗传变异也为靶向疗法和新型治疗方法的开发铺平了道路。这篇综述强调了与罕见病的基因诊断相关的挑战,并提供了未来的方向。特别关注IEI。尽管过去几年取得了巨大的进展,由于每位患者产生的遗传数据数量不断增加,一些障碍仍然存在或变得更加重要。这包括,首先,对已知IEI基因中的未知意义变异(VUS)和未知意义基因中的变异(GUS)的解释。尽管基因诊断为IEI和其他罕见疾病的理解和管理做出了重要贡献,进一步研究,来自不同临床学科的专家之间的交流,数据整合和建立全面的指南对于应对剩余的挑战和最大限度地发挥遗传诊断在罕见疾病领域的潜力至关重要,比如IEI。
New technologies in genetic diagnostics have revolutionized the understanding and management of rare diseases. This review highlights the significant advances and latest developments in genetic diagnostics in inborn errors of immunity (IEI), which encompass a diverse group of disorders characterized by defects in the immune system, leading to increased susceptibility to infections, autoimmunity, autoinflammatory diseases, allergies, and malignancies. Various diagnostic approaches, including targeted gene sequencing panels, whole exome sequencing, whole genome sequencing, RNA sequencing, or proteomics, have enabled the identification of causative genetic variants of rare diseases. These technologies not only facilitated the accurate diagnosis of IEI but also provided valuable insights into the underlying molecular mechanisms. Emerging technologies, currently mainly used in research, such as optical genome mapping, single cell sequencing or the application of artificial intelligence will allow even more insights in the aetiology of hereditary immune defects in the near future. The integration of genetic diagnostics into clinical practice significantly impacts patient care. Genetic testing enables early diagnosis, facilitating timely interventions and personalized treatment strategies. Additionally, establishing a genetic diagnosis is necessary for genetic counselling and prognostic assessments. Identifying specific genetic variants associated with inborn errors of immunity also paved the way for the development of targeted therapies and novel therapeutic approaches. This review emphasizes the challenges related with genetic diagnosis of rare diseases and provides future directions, specifically focusing on IEI. Despite the tremendous progress achieved over the last years, several obstacles remain or have become even more important due to the increasing amount of genetic data produced for each patient. This includes, first and foremost, the interpretation of variants of unknown significance (VUS) in known IEI genes and of variants in genes of unknown significance (GUS). Although genetic diagnostics have significantly contributed to the understanding and management of IEI and other rare diseases, further research, exchange between experts from different clinical disciplines, data integration and the establishment of comprehensive guidelines are crucial to tackle the remaining challenges and maximize the potential of genetic diagnostics in the field of rare diseases, such as IEI.