Department of Human Genetics, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.
Department of Internal Medicine, Radboudumc Center for Infectious Diseases (RCI), Radboudumc, Nijmegen, The Netherlands.
Clin Rev Allergy Immunol. 2021 Oct;61(2):212-225. doi: 10.1007/s12016-021-08838-5. Epub 2021 Mar 5.
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.
原发性免疫缺陷是一组先天性免疫错误，表现出显著的临床和遗传异质性。下一代测序技术，主要是全外显子组测序，彻底改变了对遗传疾病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队列中使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效果。原发性免疫缺陷的平均诊断率为 29%（范围 10-79%），而全外显子组测序的诊断率为 38%（范围 15-70%）。研究之间的显著差异主要是由于研究队列的临床特征不同所致，但也受到不同测序方法和（计算机）基因组合选择的影响。我们进一步讨论了导致相对低诊断率的其他因素，包括全外显子组测序的固有局限性、新型候选遗传变异解释的挑战，以及探索基因组非编码部分的前景。我们提出了提高诊断效果的策略，为 PID 的个体化治疗铺平道路。
