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. 2025 Jun 2;45(1):102.
doi: 10.1007/s10875-025-01896-w.

Genetics in a Danish Common Variable Immunodeficiency Cohort

Camilla Heldbjerg Drabe  1 , Mira Marie Laustsen  2 , Hanne Vibeke Marquart  3   4 , Hans Jakob Hartling  3 , Rasmus L Marvig  2 , Jannik Helweg-Larsen  5 , Ann-Brit Eg Hansen  4   6 , Jens Lundgren  7 , Marie Helleberg  5   7 , Line Borgwardt #  2 , Terese L Katzenstein #  5
Affiliations

Genetics in a Danish Common Variable Immunodeficiency Cohort

Camilla Heldbjerg Drabe et al. J Clin Immunol. .

Abstract

Purpose: 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.

Methods: 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.

Results: 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%.

Conclusion: 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.

Supplementary Information: The online version contains supplementary material available at 10.1007/s10875-025-01896-w.

Keywords: Antibody deficiency; Common variable immunodeficiency; Inborn errors of immunity; Next generation sequencing; Whole exome sequencing; Whole genome sequencing.

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Conflict of interest statement

Declarations. Ethics Approval and Consent: The study was performed according to the principles of the Declaration of Helsinki and approved by the Danish Regional Ethics Committee (H-15009663). All participants provided written informed consent. Competing Interests: CD: travel grant and speakers fee from Takeda Pharma. MH: speakers fee from AstraZeneca, Gilead, Sanofi, GSK and Leo Pharma and a research grant from AstraZeneca. LGB: consultant and speakers fee from Chiesi Farmaceutici S.p.A. AEH: travel grants and speakers fees from CSL Behring and travel grants from Takeda Pharma. TLK: personal fees and grants, including travel grants, from ViiV/Glaxo Smith Kline, Gilead, Merck Sharp & Dohme, CLS Behring, Takeda, Chiesi and Vertex. All unrelated to the current study.

Figures

Fig. 1
Fig. 1
Patient flow. PID: Primary immunodeficiency, CVID: common variable immunodeficiency, UAD: unclassified antibody deficiency, CID: combined immunodeficiency, HIGM: Hyper-IgM-Syndrome
Fig. 2
Fig. 2
Number of variants identified in the entire cohort, stratified by ACMG-classification. The figure shows the ACMG-class-distribution of variants when originally reported, and after re-evaluation. Likely benign and benign variants were not originally reported. In total 17 variants of uncertain significance (VUS) were re-classified upon re-evaluation. These variants were classified as likely pathogenic (n = 6), likely benign (n = 2) or benign (n = 3). Six variants remained of uncertain significance but were excluded according to current reporting algorithm. ACMG: American College of Medical Genetics and Genomics
See this image and copyright information in PMC

References

    1. Bousfiha A, Moundir A, Tangye SG, Picard C, Jeddane L, Al-Herz W, et al. The 2022 update of IUIS phenotypical classification for human inborn errors of immunity. J Clin Immunol. 2022;42:1508–20. - PubMed
    1. Bonilla FA, Barlan I, Chapel H, Costa-Carvalho BT, Cunningham-Rundles C, de la Morena MT, et al. International consensus document (ICON): common variable immunodeficiency disorders. J Allergy Clin Immunol Pract. 2016;4:38–59. - PMC - PubMed
    1. Katzenstein TL, Rasmussen LD, Drabe CH, Larsen CS, Hansen A-BE, Stærkind M, et al. Outcome of SARS-CoV-2 infection among patients with common variable immunodeficiency and a matched control group: a Danish nationwide cohort study. Front Immunol. 2022;13:994253. - PMC - PubMed
    1. Seidel MG, Kindle G, Gathmann B, Quinti I, Buckland M, van Montfrans J, et al. The European Society for Immunodeficiencies (ESID) registry working definitions for the clinical diagnosis of inborn errors of immunity. J Allergy Clin Immunol Pract. 2019;7:1763–70. - PubMed
    1. Westh L, Mogensen TH, Dalgaard LS, Jensen JMB, Katzenstein T, Hansen A-BE, et al. Identification and characterization of a nationwide Danish adult common variable immunodeficiency cohort. Scand J Immunol. 2017;85:450–61. - PubMed

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