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Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by hypogammaglobulinemia and recurrent infections. Despite inclusion of MS4A1 (encoding CD20) in multi‐gene panels for CVID, no MS4A1 variants meeting pathogenic criteria have been reported. In a cohort of 66 CVID patients, candidate gene sequencing focussed on CARMA1/CARD11 and Bob1 but noted that CD20 (MS4A1) variants contribute to <15% of cases ([PMID:21905497]). More recently, targeted NGS of 19 CVID‐related genes including MS4A1 in 103 unrelated probands identified 227 rare variants overall, though none in MS4A1 were classified as pathogenic; most were variants of uncertain significance or benign/likely benign ([PMID:33859323]). No family segregation of MS4A1 variants with CVID has been documented.
Functional evidence linking MS4A1 to CVID is lacking. While CD20 is essential for B‐cell development and antibody responses, no studies have assessed the impact of MS4A1 variants on immunoglobulin levels or B‐cell function in CVID patients. Alternative CD20 transcript studies in autoimmune and malignant B‐cell contexts suggest splicing and expression changes affect therapeutic antibody binding but do not directly implicate MS4A1 in CVID pathogenesis.
Overall, the genetic evidence for MS4A1 in CVID is limited: rare variants have been observed in up to 103 probands without pathogenic classification or segregation data. No experimental or clinical functional studies support a causal role. Further family‐based sequencing, segregation analysis, and B‐cell functional assays are required to clarify any contribution of MS4A1 to CVID.
Key take‐home: Current evidence does not support MS4A1 as a monogenic cause of CVID; its inclusion in diagnostic panels warrants re‐evaluation pending functional validation.
Gene–Disease AssociationLimitedNo pathogenic MS4A1 variants identified among 103 probands; no segregation data Genetic EvidenceLimitedRare MS4A1 variants detected in multi‐gene panels without classification as pathogenic or co‐segregation ([PMID:33859323]) Functional EvidenceNo Reported EvidenceNo functional studies have assessed MS4A1 variants in CVID |