GSPT2 – Intellectual Disability

Recent studies have identified Xp11.22 deletions that recurrently encompass GSPT2 in males presenting with intellectual disability, global developmental delay, hypotonia, joint hypermobility, and relative macrocephaly (PMID:31555424, PMID:28414775). These overlapping deletions, detected in independent families, suggest that loss‐of‑function of GSPT2 may be a major driver of the clinical phenotype.

The genetic evidence is supported by two independent case series reporting a total of 8 probands with similar clinical presentations. In both studies, the affected males carried overlapping deletions at Xp11.22, implicating GSPT2 along with a small set of neighboring genes. Despite the deletion being maternally inherited in some cases, the consistent presentation in males, who are hemizygous for the X‑linked gene, supports a pathogenic role for GSPT2 (PMID:31555424, PMID:28414775).

Although explicit single‐nucleotide HGVS variants were not reported, the deletion events serve as a surrogate for loss‑of‑function alterations in GSPT2. These gene disruptions fulfill key genetic criteria, with the overlapping nature of the deletions across unrelated probands providing robust genetic evidence of association (PMID:31555424, PMID:28414775).

Functional assessments have further bolstered these findings. In vitro complementation assays have demonstrated that mouse GSPT2 can substitute for yeast eRF3, a finding which underscores the functional importance of GSPT2 in translational termination (PMID:12354098). Moreover, molecular cloning studies confirmed that GSPT2 interacts with eRF1 in mammalian cells, supporting a loss‑of‑function mechanism that could explain the neurodevelopmental abnormalities observed in patients (PMID:9712840).

No conflicting evidence has been reported to date, and the experimental data are in concordance with the clinical observations. The integration of genetic and functional studies presents a compelling case for the role of GSPT2 in the pathogenesis of intellectual disability in affected males.

Key take‑home: The robust association between recurrent Xp11.22 deletions involving GSPT2 and intellectual disability supports its use as a diagnostic marker and underscores the potential for developing targeted genetic testing strategies in clinical practice.

References

• Oman medical journal • 2019 • Further Clinical and Molecular Delineation of Xp11.22 Deletion Syndrome: A Case Report PMID:31555424
• PloS one • 2017 • Xp11.22 deletions encompassing CENPVL1, CENPVL2, MAGED1 and GSPT2 as a cause of syndromic X‑linked intellectual disability PMID:28414775
• Genes to cells : devoted to molecular & cellular mechanisms • 2002 • Mouse GSPT2, but not GSPT1, can substitute for yeast eRF3 in vivo PMID:12354098
• The Journal of biological chemistry • 1998 • Molecular cloning of a novel member of the eukaryotic polypeptide chain‑releasing factors (eRF) PMID:9712840

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