Submission Details

*FASLG *(i.e., FAS ligand) was originally reported in relation to autosomal dominant autoimmune lymphoproliferative sydrome (ALPS) by by Wu et al. in 1996 (PMID: 8787672). Autoimmune lymphoproliferative syndrome is a disease characterized by signs of lymphoproliferation including lymphadenopathy and splenomegaly, as well as features of autoimmunity, often including combs positive hemolytic anemia. Biomarkers of the disease include increased IgG, increased Il-10, increased serum B12, and a very notable increase in the number of double negative T cells. There is a significantly elevated risk for Hodgkin lymphoma and there is an additional risk for other autoimmune diseases such as glomerulonephritis or autoimmune hepatitis. Similar to FAS variants, which are the most common cause of ALPS, it was originally thought that heterozygous FASLG variants were associated with ALPS. However, previously characterized patients with heterozygous variants did not display double negative T cells or other biomarkers characteristic of the disease (PMID: 8787672 and PMID: 17605793). Additionally, an in depth review from Maccari et al., PMID: 36621650, found that disease carriers had normal FasL-mediated cytotoxicity in patient T cells.

More than 7 homozygous variants (missense and frameshift) in 7 probands have been reported to cause ALPS due to FASLG deficiency to date (PMID: 25451160, 22857792, 26334989, 16627752, 26456038, 36621650). The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by animal models, the biochemical function of FAS/FASL signaling, and cell culture models. From Karray S, et al., (PMID: 14764677) FASL (-/-) mice recapitulate several key features of patients with bi-allelic FASLG loss of function variants. Notably, FASLG knock out mice and probands both demonstrated phenotypes such as lymphadenopathy, hepatosplenomegaly, a greatly increased percentage of double negative T cells, increased Igg, and failure to thrive. Further experimental evidence comes from the well characterized role of FAS/FASL signaling in CD8 cytotoxic T cell function and activation induced cell death, which through apoptosis limits the number of clonal T cells after antigen elimination and importantly eliminates autoreactive T cells that have evaded self-reactivity screening in the thymus by negative selection. Failure of the FAS/FASLG pathway results lymphoproliferation and autoimmunity due to defective signaling that fails to eliminate auto-reactive T cells and fails to curve the immune response after antigen elimination. Finally, experimental evidence is supported by FASL deficient lymphocytes which display defective cytotoxic activity and impaired FAS/FASL signaling Lowin B, et al., PMID: 7520535.

In summary, there is definitive evidence supporting the relationship between FASLG and autosomal recessive autoimmune lyphoproliferative syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.