SLC35C1 – Leukocyte Adhesion Deficiency Type II

Leukocyte adhesion deficiency type II (Leukocyte Adhesion Deficiency Type II) is an autosomal recessive inherited disorder characterized by impaired leukocyte rolling and recurrent infections due to deficient fucosylation of selectin ligands. Variants in the GDP-fucose transporter gene SLC35C1 disrupt GDP-fucose import into the Golgi, leading to altered glycoform distributions. Patients present with leukocytosis, periodontitis, short stature, global developmental delay, and Bombay blood phenotype. Clinical variability ranges from classical immunodeficiency to attenuated forms with isolated growth delay and cognitive impairment. The severe form manifests with pronounced neutrophilia and recurrent severe infections, whereas milder variants show minimal adhesion defects. This summary synthesizes genetic and functional evidence for the SLC35C1–LAD II association to support diagnostic and therapeutic decision-making.

Through four independent reports, a total of six unrelated probands with autosomal recessive inheritance have been described (6 probands (PMID:24403049, PMID:32992000, PMID:35338746, PMID:32313197)). Segregation analysis in one sib pair confirmed compound heterozygosity in two affected brothers (PMID:24403049), yielding one additional affected relative. Variants include three predicted loss-of-function alleles (c.91G>T (p.Glu31Ter), c.247_249del (p.Val83del), c.367del) and three in-frame deletions or missense changes (c.177_179del (p.Asn59del), c.503_505del (p.Phe168del), c.891T>G (p.Asn297Lys)). Recurrent p.Phe168del has been observed in two families, suggesting a possible founder or genotype–phenotype correlation (PMID:32313197). Carrier frequency is not established, but oral fucose responsiveness indicates residual transporter activity in milder cases. These findings support a robust genetic basis for SLC35C1 in LAD II.

In functional studies, plasma glycoprotein analyses demonstrated marked reductions in core fucosylation and sialyl Lewis X epitopes (PMID:24403049). Neutrophil rolling assays revealed partial impairment of endothelial selectin binding, yet residual adhesion ameliorated severe leukocytosis (PMID:24403049). Oral l-fucose supplementation in attenuated cases improved CD15 expression, core fucosylation, speech, and cognitive outcomes after 27 months (PMID:35338746). In a Bombay phenotype patient, fucose therapy led to resolution of skin infections and behavioral improvements (PMID:32992000). These concordant functional and therapeutic data validate haploinsufficiency of fucose transport as the pathogenic mechanism.

Phenotypic variability, including isolated short stature and intellectual disability without overt immunodeficiency, expands the clinical spectrum (PMID:32313197). In attenuated phenotypes, minimal adhesion defects contrast with classical neutrophilia, underscoring residual GDP-fucose transport capacity. No studies have refuted the SLC35C1–LAD II link, and no population variants have challenged pathogenicity. Overall, genotype–phenotype correlations align with variant impact on transporter function, with loss-of-function alleles causing classical disease and hypomorphic alleles mediating milder forms.

Integrating genetic and functional evidence yields a strong association between biallelic SLC35C1 variants and leukocyte adhesion deficiency type II. Autosomal recessive inheritance, multiple unrelated probands, concordant segregation, and functional impairment of fucosylation underpin gene–disease causality. Oral fucose therapy responses in attenuated cases demonstrate both diagnostic validation and potential treatment avenues. While additional model organism data could strengthen the evidence base, current findings suffice for a Strong ClinGen classification. Clinical screening for SLC35C1 variants is recommended in patients with growth delay, developmental issues, and recurrent infections. Key Take-home: Genetic testing for SLC35C1 and prompt l-fucose therapy can guide diagnosis and improve outcomes in LAD II.

References

• Human Molecular Genetics • 2014 • Congenital disorder of fucosylation type 2c (LADII) presenting with short stature and developmental delay with minimal adhesion defect. PMID:24403049
• Clinical Immunology • 2020 • Incidental diagnosis of leukocyte adhesion deficiency type II following ABO typing. PMID:32992000
• American Journal of Medical Genetics Part A • 2022 • Defining the mild variant of leukocyte adhesion deficiency type II (SLC35C1-congenital disorder of glycosylation) and response to l-fucose therapy: Insights from two new families and review of the literature. PMID:35338746
• Journal of Human Genetics • 2020 • Biallelic variants in SLC35C1 as a cause of isolated short stature with intellectual disability. PMID:32313197

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