Glycosylphosphatidylinositol is a glycolipid that anchors more than 150 proteins to the cell surface, and these proteins, termed GPI-anchored proteins (GPI-APs), perform a variety of functions as enzymes, adhesion molecules, complement regulators, and coreceptors in signal transduction pathways. Reduced surface levels of GPI-APs or abnormal GPI-AP structure can therefore result in variable manifestations. Glycosylphosphatidylinositol biosynthesis defect-1 (GPIBD1) is characterized predominantly by portal hypertension due to portal vein thrombosis. Most patients have absence seizures, cerebral thrombosis, and macrocephaly. Some patients have mildly to moderately impaired intellectual development (summary by Makrythanasis et al., 2016; Pode-Shakked et al., 2019). Genetic Heterogeneity of Glycosylphosphatidylinositol Biosynthesis Defects Also see GPIBD2 (239300), caused by mutation in the PIGV gene (610274); GPIBD3 (614080), caused by mutation in the PIGN gene (606097); GPIBD4 (300868), caused by mutation in the PIGA gene (311770); GPIBD5 (280000), caused by mutation in the PIGL gene (605947); GPIBD6 (614749), caused by mutation in the PIGO gene (614730); GPIBD7 (615398), caused by mutation in the PIGT gene (610272); GPIBD8 (614207), caused by mutation in the PGAP2 gene (615187); GPIBD9 (615802), caused by mutation in the PGAP1 gene (611655); GPIBD10 (615716), caused by mutation in the PGAP3 gene (611801); GPIBD11 (616025), caused by mutation in the PIGW gene (610275); GPIBD12 (616809), caused by mutation in the PIGY gene (610662); GPIBD13 (616917), caused by mutation in the PIGG gene (616918); GPIBD14 (617599), caused by mutation in the PIGP gene (605938); GPIBD15 (617810), caused by mutation in the GPAA1 gene (603048); GPIBD16 (617816), caused by mutation in the PIGC gene (601730); GPIBD17 (618010), caused by mutation in the PIGH gene (600154); GPIBD18 (618143), caused by mutation in the PIGS gene (610271); GPIBD19 (618548), caused by mutation in the PIGQ gene (605754); GPIBD20 (618580), caused by mutation in the PIGB gene (604122); GPIBD21 (618590), caused by mutation in the PIGU gene (608528); GPIBD22 (618879), caused by mutation in the PIGK gene (605087); GPIBD23 (617020), caused by mutation in the ARV1 gene (611647); GPIBD24 (619356), caused by mutation in the PIGF gene (600153); and GPIBD25 (619985), caused by mutation in the C18ORF32 gene (619979).

WHIM syndrome-1 (WHIMS1) is an autosomal dominant immunologic disorder characterized by neutropenia, hypogammaglobulinemia, and warts due to human papillomavirus (HPV) infection. Despite the peripheral neutropenia, bone marrow aspirates from affected individuals contain abundant mature myeloid cells, a condition termed myelokathexis. The susceptibility to HPV is disproportionate compared with other immunodeficiency conditions (summary by Hernandez et al., 2003). Heusinkveld et al. (2019) provided a detailed review of the clinical features, proposed pathogenesis, and possible therapeutic treatments of WHIM syndrome. There is significant phenotypic variation among patients, such that some individuals may have an 'incomplete' form of the disorder in which one or more of the classic tetrad features are not present. In general, the WHIMS phenotype comprises a spectrum of manifestations with variable expressivity. The pathogenesis of WHIMS1 is postulated to result from impaired CXCL12 (600835)-induced internalization of CXCR4, resulting in prolonged receptor presence at the cell surface that likely contributes to amplification of signaling with a gain-of-function effect. Genetic Heterogeneity of WHIM Syndrome See also WHIMS2 (619407), caused by mutation in the CXCR2 gene (146928) on chromosome 2q35.