Submission Details

The relationship between MS4A1 and Common Variable Immunodeficiency 5, an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of July, 2021. MS4A1 encodes a member of the membrane-spanning 4A gene family, a B-lymphocyte surface molecule, CD20, which plays a role in the development and differentiation of B-cells into plasma cells. Common Variable Immunodeficiency, also referred to as CD20 deficiency, is characterized by persistently low levels of IgG and recurrent respiratory infections (Kuijpers et al; PMID: 20038800). CD20 is expressed on all B cells from the late pre-B cell stage to memory B cells. It is not expressed on terminally differentiated plasmablasts and plasma cells, except in the context of certain B cell malignancies. CD20 deficiency is exceedingly rare, but based on a single report appears to affect peripheral B cell differentiation. CD20 has been shown to regulate signaling through the B cell receptor (BCR). CD20 is a popular therapeutic target for B cell depletion in malignancies, autoimmunity, and other immune dysregulatory conditions (PMIDs: 32482755, 33563755, 32210425). There may be a hierarchical loss of immunoglobulin isotypes after B cell depletion with anti-CD20 therapeutic antibodies with some isotypes, such as IgM and IgG being more affected than IgA (PMID: 23136242). MS4A1 was first reported in relation to autosomal recessive common variable immunodeficiency 5 in 2010 (Kuijpers et al, PMID: 20038800). Bogaert et al, 2016 (PMID: 27250108) reported that this patient did not completely fulfil diagnostic criteria for CVID. To date, this is the only patient that has been reported with a loss-of-function variant in MS4A1 and a positive disease association. There is limited evidence supporting this gene-disease relationship including case-level data and experimental data.

Summary of Case Level Data (3 points): There has been 1 patient from 1 publication, till date, reported with a homozygous variant in MS4A1 (PMID: 20038800). The mechanism of disease is expected to be biallelic loss of function.

Summary of experimental data (2 points): This gene-disease relationship is supported by animal model and expression evidence. MS4A1 is specifically expressed on B-lymphocytes and functions as part of the B-cell surface complex involved in transmembrane Ca2+ transport (PMID: 14688067). Knock-out of MS4A1 in two mouse models showed that mice had a defect in B-cell maturation and defective Ca2+ transport (PMID: 23966626, 14688067) and partially recapitulate the human phenotype.

In summary, the level of evidence to support the gene-disease relationship of MS4A1 and autosomal recessive Common Variable Immunodeficiency 5 is limited. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged.