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Next-Generation Sequencing in the Field of Primary Immunodeficiencies: Current Yield, Challenges, and Future Perspectives
Clinical Reviews in Allergy & Immunology ( IF 9.1 ) Pub Date : 2021-03-05 , DOI: 10.1007/s12016-021-08838-5
Emil E Vorsteveld 1 , Alexander Hoischen 1, 2, 3 , Caspar I van der Made 1, 2, 3
Affiliation  

Primary immunodeficiencies comprise a group of inborn errors of immunity that display significant clinical and genetic heterogeneity. Next-generation sequencing techniques and predominantly whole exome sequencing have revolutionized the understanding of the genetic and molecular basis of genetic diseases, thereby also leading to a sharp increase in the discovery of new genes associated with primary immunodeficiencies. In this review, we discuss the current diagnostic yield of this generic diagnostic approach by evaluating the studies that have employed next-generation sequencing techniques in cohorts of patients with primary immunodeficiencies. The average diagnostic yield for primary immunodeficiencies is determined to be 29% (range 10–79%) and 38% specifically for whole-exome sequencing (range 15–70%). The significant variation between studies is mainly the result of differences in clinical characteristics of the studied cohorts but is also influenced by varying sequencing approaches and (in silico) gene panel selection. We further discuss other factors contributing to the relatively low yield, including the inherent limitations of whole-exome sequencing, challenges in the interpretation of novel candidate genetic variants, and promises of exploring the non-coding part of the genome. We propose strategies to improve the diagnostic yield leading the way towards expanded personalized treatment in PIDs.



中文翻译:

原发性免疫缺陷领域的下一代测序:当前产量、挑战和未来前景

原发性免疫缺陷包括一组先天性免疫缺陷,表现出显着的临床和遗传异质性。下一代测序技术和主要的全外显子组测序彻底改变了对遗传疾病的遗传和分子基础的理解,从而也导致与原发性免疫缺陷相关的新基因的发现急剧增加。在这篇综述中,我们通过评估在原发性免疫缺陷患者群体中采用下一代测序技术的研究,讨论了这种通用诊断方法的当前诊断率。原发性免疫缺陷的平均诊断率为 29%(范围 10-79%),全外显子组测序的平均诊断率为 38%(范围 15-70%)。研究之间的显着差异主要是由于研究队列的临床特征差异造成的,但也受到不同测序方法和(计算机上)基因组选择的影响。我们进一步讨论了导致产量相对较低的其他因素,包括全外显子组测序的固有局限性、解释新候选遗传变异的挑战以及探索基因组非编码部分的承诺。我们提出了提高诊断率的策略,从而引导扩大 PID 的个性化治疗。

更新日期:2021-03-05
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