Genetics in a Danish Common Variable Immunodeficiency Cohort

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.