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A biallelic loss-of-function mechanism in ICOSLG has been implicated in autosomal recessive combined immunodeficiency. A single unrelated patient exhibited recurrent respiratory and DNA-based viral infections, hypogammaglobulinemia, panlymphopenia and moderate neutropenia. Whole-exome sequencing identified a homozygous missense variant, c.657C>G (p.Asn219Lys), that segregated with disease in the index case ([PMID:30498080]).
Functional assays demonstrated that ICOSL^Asn219Lys is retained in the endoplasmic reticulum/Golgi, abolishing cell surface localization and severely impairing B cell costimulation of T cells as well as lymphocyte and neutrophil transendothelial migration. These findings provide mechanistic concordance with the observed antibody deficiency and neutropenia, supporting pathogenicity of the variant ([PMID:30498080]).
Key Take-home: Genetic screening of ICOSLG should be considered in patients with hypogammaglobulinemia, panlymphopenia and recurrent infections to enable precise diagnosis and tailored management.
Gene–Disease AssociationLimitedSingle proband without extended segregation ([PMID:30498080]) Genetic EvidenceLimitedSingle homozygous variant in one proband, AR inheritance ([PMID:30498080]) Functional EvidenceModerateIn vitro assays show loss of ICOSL surface expression, impaired B cell costimulation and leukocyte migration ([PMID:30498080]) |