CD40LG was first reported in relation to X-linked hyper IgM (HIGM) syndrome in 1993 by multiple groups independently (Korthauer et al., PMID: 7679206; DiSanto et al., PMID: 8094231; Allen et al., PMID: 7679801; Aruffo et al., PMID: 7678782). CD40LG encodes the protein CD40 ligand, a transmembrane molecule found on T cells. HIGM syndrome is a primary immunodeficiency disorder caused by defective immunoglobulin class switch recombination. It is characterized by decreased levels of certain immunoglobulins including IgG, IgA, and IgE with normal or increased levels of IgM. These deficiencies increase susceptibility to severe and opportunistic infections that can be recurrent and life threatening. HIGM syndrome due to CD40 ligand deficiency occurs almost exclusively in males. Heterozygous females typically are asymptomatic with normal levels of immunoglobulins (PMID: 7518839), although rare cases of clinically affected female carriers have been reported when X chromosome inactivation is skewed (PMID: 9933119, 16311023). Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least 16 variants (e.g. missense, in-frame indel, nonsense, frameshift, large deletion, complex rearrangement, etc.) have been reported in at least 16 probands in 7 publications (PMID: 7679206, 8094231, 7679801, 7678782, 9933119, 15358621, 15997875). Many are loss of function variants, establishing this as the molecular mechanism of the condition. This gene-disease association is supported by expression studies, in vitro functional assays, animal models, and rescue assays (PMID: 1280226, 7964465, 7882172, 26903548, 29847792, 33475257, 21285457). More evidence is available in the literature, but the maximum score for genetic evidence and experimental evidence (18 pts.) has been reached. In summary, CD40LG is definitively associated with X-linked recessive hyper IgM syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen SCID/CID Working Group on DATE (SOP Version 8).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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