Submission Details

The relationship between ICOSLG and Combined Immunodeficiency, an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of April, 2023. Features of combined immunodeficiency due to ICOSLG variants include recurrent infections, panhypogammaglobulinemia and pneumonia. ICOSLG is an important protein that plays a role in regulating T- Cells. ICOSLG is expressed on antigen presenting cells while ICOS is expressed on T- Cells. The two interact to secrete cytokines that promote proliferation and differentiation of T- Cells, enhancing the immune response (Roussel, et al; PMID: 30498080). Patients with autosomal recessive NIK deficiency (MAP3K14 gene) have low ICOSL as this is regulated by NIK (PMID: 21768353 and PMID: 25406581). ICOSLG was first reported in relation to autosomal recessive combined immunodeficiency in 2018 (Roussel L 2018, PMID: 30498080).

Summary Case Level Data (2 points): Variants in this gene have been reported in at least two individuals from two publications, both of French Canadian origin (PMID: 30498080, 34694545). Both individuals were homozygous for the missense variant in ICOSLG, Asn219Lys. Although only two apparently unrelated individuals have been reported with the same missense variant, each proband was scored the full 1 point due to the potential for a common founder variant in the French Canadian population, similar to ICOS deficiency.

EXPERIMENTAL EVIDENCE (5 points): This gene-disease association is supported by a mouse model and functional assays. Icosl-/- mice show reduced antibody production and impaired helper T cell differentiation. Icosl-/- mice developed attenuated allergic airway disease and showed an interference with the B- Cell isotype class switching (Mak, et al; PMID: 12833154).

ICOSL binds to the receptor ICOS and this interaction is critical for the maturation of germinal center B cells to affinity-matured memory B cells and long-lived plasma cells.

This gene-disease association is supported by functional alteration; the authors cocultured Jurkat cells activated by TNFα to induce ICOS expression and measure gene responses of cytokines. This showed that there was a significant reduction in of the expression of ICOSL protein on the cell surface. The variant transfected into HMEC1 cells resulted in defective transendothelial migration of T cells and neutrophils (Roussel, et al; PMID: 3049808).

In summary, the level of evidence to support the gene-disease relationship of ICOSLG and autosomal recessive Combined Immunodeficiency is moderate. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. The interaction of ICOSL with ICOS to promote proliferation and differentiation of T- Cells, enhancing the immune response, is well understood. ICOS deficiency is well described and the ICOS- Common Variable Immunodeficiency gene disease relationship is definitive. Based on ICOS and ICOSL belonging to the same pathway, the Antibody Deficiencies GCEP determined that the ICOSL- Combined Immunodeficiency relationship should reach a moderate classification. This classification was approved by the Antibody Deficiencies GCEP on April 25th, 2023 (SOP v9).