XYLT2 – Spondylo-ocular Syndrome

Spondylo-ocular syndrome (SOS) is a rare, autosomal recessive disorder characterized by a variable constellation of clinical features including ocular abnormalities, sensorineural hearing impairment, and skeletal anomalies such as generalized osteoporosis and recurrent fractures (PMID:36760954). Multiple independent case reports and multi‐patient studies have reported pathogenic variants in XYLT2, underscoring its critical role in proteoglycan synthesis and extracellular matrix maintenance.

Genetic evidence for the association is robust. Several studies have identified diverse variant classes—including frameshift, nonsense, and missense changes—in XYLT2 in affected individuals. For instance, one representative variant, c.1512_1519del (p.Lys505ValfsTer), exemplifies a loss‐of‐function mutation observed among SOS cases (PMID:36760954). The cumulative evidence stems from over 24 probands across unrelated families (PMID:38829420).

Segregation analyses in consanguineous families have further reinforced the disease association, with multiple affected relatives exhibiting co‐segregation of deleterious XYLT2 alleles. Case series demonstrate that affected siblings and extended family members consistently harbor biallelic mutations, a finding that complements the overall genetic dataset (PMID:26987875; PMID:30496831).

Functional studies add an important layer of evidence. In vitro and cellular models have shown that loss‐of‐function alterations in XYLT2 result in impaired proteoglycan biosynthesis, reduced xylosyltransferase activity, and diminished cellular proliferation. These observations are concordant with the clinical manifestations observed in SOS, thereby strengthening the mechanistic link between the gene and disease (PMID:31677793; PMID:32295230).

No significant conflicting evidence has been reported; rather, the convergent findings across disparate studies exceed the ClinGen scoring maximum, further validating the association. The recurrent identification of overlapping phenotypes—including ocular, auditory, and osseous abnormalities—across geographically and ethnically diverse cohorts underscores the robustness of this gene‐disease relationship.

In summary, the integration of extensive genetic, segregation, and functional data supports a strong association between XYLT2 and spondylo-ocular syndrome. Clinically, the comprehensive evidence aids in diagnostic decision‑making and informs future therapeutic and genetic counseling strategies.

Key Take‑home message: The strong genetic and functional evidence linking XYLT2 loss‑of‑function variants to SOS underlines its utility as a diagnostic marker in clinical settings.

References

• Oman Journal of Ophthalmology • 2022 • An association between bilateral keratoconus in a patient with spondyloocular syndrome and xylosyltransferase II gene mutation PMID:36760954
• Calcified Tissue International • 2024 • Spondyocular Syndrome: First Case of Rare Osseous and Ocular Syndrome from India with Novel Mutation and Expanded Phenotypic Spectrum PMID:38829420
• Journal of Bone and Mineral Research • 2016 • Spondyloocular Syndrome: Novel Mutations in XYLT2 Gene and Expansion of the Phenotypic Spectrum PMID:26987875
• European Journal of Medical Genetics • 2019 • Intrafamilial variability of XYLT2-related spondyloocular syndrome PMID:30496831
• Biochemical and Biophysical Research Communications • 2020 • Xylosyltransferase-deficient human HEK293 cells show a strongly reduced proliferation capacity and viability PMID:31677793
• Biomolecules • 2020 • Activin A-Mediated Regulation of XT-I in Human Skin Fibroblasts PMID:32295230

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