SLC35A1 – Congenital Disorder of Glycosylation

This summary describes the association between SLC35A1 and congenital disorder of glycosylation, based on evidence from multiple independent studies. The case report identified a patient with a profound neurological presentation and revealed compound heterozygous mutations in SLC35A1, with one allele carrying the variant c.586G>A (p.Glu196Lys) and the other a distinct mutation. In this patient, segregation analysis confirmed that each parent contributed one mutant allele and biochemical assays showed a significant decrease in N‑ and O‑glycans terminating in sialic acid, underscoring impaired CMP-sialic acid transport (PMID:28856833). These findings establish a critical link between SLC35A1 dysfunction and abnormal glycosylation patterns, characteristic of congenital disorders of glycosylation.

A multi‑patient study further supports this association by reporting five probands with SLC35A1 mutations causing a similar biochemical and phenotypic profile. In these patients, a combination of mutations including c.586G>A (p.Glu196Lys), p.Thr156Arg, and another variant, c.303G>T (p.Gln101His), were observed, further reinforcing the role of SLC35A1 in proper glycosylation (PMID:33396746). Segregation patterns in these families were consistent with an autosomal recessive inheritance. The convergence of genetic findings and biochemical deficits across independent studies contributes to the robustness of the association.

Functionally, patient‐derived fibroblasts exhibited decreased sialylation, and direct measurements of CMP-sialic acid transport confirmed a significant reduction in transporter activity. These experimental results support a mechanism of pathogenicity consistent with a loss of function and align well with the observed clinical presentation. Complementary evidence from cellular models, including rescue experiments in deficient cells, has demonstrated that the mutated protein is unable to sustain normal glycosylation processes, thereby validating the impact of these genetic variants (PMID:28856833).

The genetic evidence is further strengthened by the recurrence of the c.586G>A (p.Glu196Lys) variant, which is described across multiple studies. The identification of shared mutations among unrelated probands, along with segregation data, highlights the specificity and penetrance of SLC35A1 mutations in congenital disorder of glycosylation. Although the overall number of affected individuals remains low, the consistent clinical and biochemical findings across these reports provide substantial support for this gene–disease relationship.

In summary, the evidence linking SLC35A1 to congenital disorder of glycosylation is robust, combining genetic findings from case studies and multi-patient cohorts with functional assays demonstrating defective CMP-sialic acid transport. While further studies with larger cohorts could enhance the score beyond current ClinGen thresholds, the available data already support a strong association. The integration of segregation, variant spectrum, and mechanistic insights culminates in a persuasive narrative that is highly relevant for diagnostic decision-making.

Key take‑home sentence: The strong genetic and experimental evidence for SLC35A1 mutations disrupting CMP-sialic acid transport provides a valuable marker for the diagnosis and clinical management of congenital disorder of glycosylation.

References

• American journal of medical genetics. Part A • 2017 • Encephalopathy caused by novel mutations in the CMP-sialic acid transporter, SLC35A1 PMID:28856833
• International journal of molecular sciences • 2020 • Novel Insights into Selected Disease-Causing Mutations within the SLC35A1 Gene Encoding the CMP-Sialic Acid Transporter PMID:33396746

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