Drabe Camilla Heldbjerg, Laustsen Mira Marie, Marquart Hanne Vibeke, Hartling Hans Jakob, Marvig Rasmus L, Helweg-Larsen Jannik, Hansen Ann-Brit Eg, Lundgren Jens, Helleberg Marie, Borgwardt Line, Katzenstein Terese L
Department of Infectious Diseases, Copenhagen University Hospital, Rigshospitalet, Esther Møllers Vej 6, Copenhagen Ø, 2100, Denmark.
Department of Genomic Medicine, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
J Clin Immunol. 2025 Jun 2;45(1):102. doi: 10.1007/s10875-025-01896-w.
Genetics of Common Variable Immunodeficiency (CVID) is complex and not fully elucidated. This study presents the clinical and genetic findings of a Danish CVID cohort and investigate whether initial genetic findings can be re-classified upon re-evaluation years later in time.
From 2016 to 2021, individuals with CVID or a CVID-like-phenotype were examined using whole exome or whole genome sequencing in combination with comprehensive gene-panels. The results were re-evaluated to ensure up-to-date American College of Medical Genetics and Genomics (ACMG) classification after a median of 3.9 years. Further, a clinical-interpretation-algorithm is proposed.
Of 69 enrolled individuals, 57 met the current ESID-CVID-criteria of whom 29 (51%) had a genetic find. In total 67 ACMG class 3 to 5 variants were detected in 39 different genes. Class 3 variants (variants of uncertain significance (VUS)) accounted for 81% in the initial analysis. Upon re-evaluation 17 of 54 (31%) of the originally reported VUS were re-classified to a different ACMG-class or excluded. The developed clinical-interpretation-algorithm demonstrated high interobserver-agreement. A “definite/probable” disease causing (or contributing) genetic variant was found in 19% of the CVID-cohort and a “possible” in 18%.
A genetic cause of CVID could be identified in a minority of CVID-individuals, whereas the majority had no or uncertain genetic findings. Re-evaluation of genetic results over time is recommended, though VUS remain a significant challenge in CVID-genetics. Therefore, continued research in both CVID-genetics and in non-genetic causes of CVID is needed.
The online version contains supplementary material available at 10.1007/s10875-025-01896-w.
常见变异型免疫缺陷（CVID）的遗传学较为复杂，尚未完全阐明。本研究展示了丹麦CVID队列的临床和遗传学发现，并调查了多年后重新评估时最初的遗传学发现是否可以重新分类。
2016年至2021年，对患有CVID或CVID样表型的个体进行全外显子组或全基因组测序，并结合综合基因面板进行检测。在中位时间3.9年后，对结果进行重新评估，以确保符合最新的美国医学遗传学与基因组学学会（ACMG）分类标准。此外，还提出了一种临床解释算法。
在69名登记个体中，57名符合当前欧洲免疫缺陷学会（ESID）-CVID标准，其中29名（51%）有遗传学发现。在39个不同基因中总共检测到67个ACMG 3至5类变异。在初始分析中，3类变异（意义未明变异（VUS））占81%。重新评估时，最初报告的54个VUS中有17个（31%）被重新分类为不同的ACMG类别或被排除。所开发的临床解释算法显示出较高的观察者间一致性。在19%的CVID队列中发现了“确定/可能”的致病（或促成）基因变异，18%的队列中发现了“可能”的致病基因变异。
少数CVID个体可确定遗传病因，而大多数个体无遗传发现或遗传发现不确定。建议对遗传结果进行长期重新评估，不过VUS在CVID遗传学中仍然是一个重大挑战。因此，需要继续开展CVID遗传学和CVID非遗传病因的研究。
在线版本包含可在10.1007/s10875-025-01896-w获取的补充材料。
