Leukocyte Adhesion Deficiency Type 2 (LADII) via the SLC35C1 Gene

Leukocyte adhesion deficiency (LAD) is characterized by the inability of leukocytes, particularly neutrophils, to adhere to sites of inflammation in response to bacterial-derived attractants, cytokines, and other host-derived signals. Consequently, patients with LAD suffer from recurrent, severe infections. LAD is a consequence of defective adhesion molecule function: LADI (OMIM 116920) and LADIII (OMIM 612840) from defective integrin function, and LADII (OMIM 266265) from defective selectin function (Wild et al. Cells Tissues Organs 172:161-173, 2002). LADII (aka congenital disorder of glycosylation IIc) belongs to a group of hereditary carbohydrate-deficient glycoprotein syndromes (CDGS) characterized by impaired glycosylation of newly synthesized glycoproteins. A systemic defect in fucose metabolism results in the loss of fucosylated selectin ligands that under normal conditions are expressed on neutrophils and are required for tethering to the endothelium during the immune response (Tyrrell et al. PNAS 88:10372 -10376, 1991). Patients with LADII have high neutrophil counts and normal opsonophagocytic and bactericidal activity; however, neutrophil migration is defective (Etzioni et al. N Engl J Med 327:1789-1792, 1992). The clinical course of deficient neutrophil adhesion is milder in LADII than in other forms of LAD; however, LADII patients present other abnormal features including severe mental and growth retardation and distinctive facial features, and they lack the Lewis blood group antigens Lea and Leb as well as the H blood group antigen, a fucosylated carbohydrate (Bombay phenotype; Etzioni et al. 1992). Thus, fucosylated glycoconjugates appear to be important for mental and psychomotor development as well as the immune response. There is some evidence that oral doses of fucose can reverse some effects of LADII (Marquardt et al. Blood 94:3976-3985, 1999), but such treatment may not be effective in all LADII patients (Etzioni et al. Blood 95:3641-3643, 2000).

LADII is caused by recessive variants in the SLC35C1 gene which encodes a GDP-fucose transporter located on Golgi vesicles (Lühn et al. Nat Genet 28:69-72, 2001; Lübke et al. Nat Genet 28:73-76, 2001). To date, 4 missense variants and one small deletion represent the only causative variants reported in the SLC35C1 gene (Lübke et al. 2001; Gazit et al. J Clin Immunol 30:308-313, 2010; Helmus et al. Blood 107:3959, 2006; van de Vivjer et al. Blood Cells Mol Dis 48:53, 2012; Hidalgo et al. Blood 101:1705).

LADII is a rare form of LAD that represents a small fraction of all cases.

This test provides full coverage of all coding exons of the SLC35C1 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as >20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).