SSR4 – SSR4-related Congenital Disorder of Glycosylation

Congenital disorder of glycosylation type Iy (SSR4-CDG, MONDO:0010490) is an X-linked recessive glycosylation defect caused by pathogenic variants in SSR4 (HGNC:11326). Since the initial description, a total of 14 unrelated male patients have been reported with hemizygous SSR4 variants (PMID:36386804). Clinical manifestations uniformly include global developmental delay, intellectual disability, microcephaly, hypotonia, and distinctive facial dysmorphism.

Genetic evidence supporting a strong gene–disease relationship includes the identification of both truncating and splice-site mutations in independent cohorts. To date, 11 distinct SSR4 variants have been described in 14 patients, including a canonical donor splice-site variant c.67+2T>C that activates a cryptic GC splice donor (PMID:39653760). Recurrent loss-of-function alleles such as c.269G>A (p.Trp90Ter) have been observed de novo or segregating in affected families, confirming pathogenicity.

Although segregation data are limited, all reported variants are absent from population databases and co-segregate with disease in available pedigrees. No unaffected male carriers have been identified, consistent with hemizygous X-linked inheritance.

Functional assays provide moderate evidence of pathogenicity. The c.67+2T>C splice variant induces retention of 46 bp of intron 1, leading to a premature termination codon, activation of nonsense-mediated mRNA decay, and markedly reduced SSR4 expression in patient cells (PMID:39653760). Similarly, the p.Trp90Ter variant yields significantly decreased SSR4 mRNA levels by quantitative PCR (PMID:36386804).

No studies to date have disputed the causal role of SSR4 variants in CDG-Iy. The integration of genetic, biochemical, and cellular data establishes a consistent loss-of-function mechanism. Genetic testing for SSR4 should be included in diagnostic panels for congenital glycosylation disorders.

Key Take-home: Hemizygous loss-of-function and splice-site SSR4 variants cause X-linked CDG-Iy, with robust functional validation supporting clinical utility of molecular testing.

References

• Journal of human genetics • 2025 • Intron retention caused by a canonical splicing variant in SSR4-related congenital disorder of glycosylation. PMID:39653760
• Frontiers in genetics • 2022 • Case Report: The novel hemizygous mutation in the SSR4 gene caused congenital disorder of glycosylation type iy: A case study and literature review. PMID:36386804

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