GSX2 – Diencephalic-Mesencephalic Junction Dysplasia Syndrome

Recent evidence supports a strong association between variants in GSX2 and diencephalic‐mesencephalic junction dysplasia syndrome, a rare neurogenetic disorder characterized by global developmental delay, hypotonia, and spasticity (PMID:39119454). In the reported study, molecular analyses in a third family identified a novel GSX2 variant, reinforcing the contribution of this gene to the malformative spectrum of the disorder.

Genetic evaluation in the case series revealed that GSX2 variants follow an autosomal recessive inheritance pattern. The index family carrying the novel variant, c.747G>C (p.Trp249Cys), exhibited a clinical phenotype consistent with diencephalic‐mesencephalic junction dysplasia, with supportive observations on neuroimaging and clinical features (PMID:39119454). Although detailed segregation data (i.e. additional affected relatives) were not extensively reported, the identification of this variant in a familial context adds to the cumulative genetic evidence.

At the molecular level, the variant c.747G>C (p.Trp249Cys) represents a complete coding change with both nucleotide and protein consequences. The mutation is predicted to result in a disruption of GSX2 function, an observation that is consistent with the autosomal recessive mode of inheritance and the loss‐of‐function mechanism observed in similar neurodevelopmental disorders (PMID:39119454).

Functional studies further buttress the clinical findings. Mouse models of GSX2 deficiency and studies examining altered DNA binding have demonstrated that GSX2 pathogenic variants impair proper neuronal differentiation and basal ganglia development. In particular, a hypomorphic GSX2 variant was shown to compromise DNA interaction in vitro and recapitulate aspects of the brain malformation seen in affected individuals (PMID:39882631).

Integrating both the genetic and experimental data, the overall gene‐disease association is deemed strong as the evidence arises from a molecular examination of a novel variant in a familial context and is complemented by in vivo functional modeling. This comprehensive evidence supports the diagnostic utility of GSX2 variant analysis in patients suspected of diencephalic‐mesencephalic junction dysplasia syndrome.

Key take‐home sentence: GSX2 variant analysis, particularly the identification of c.747G>C (p.Trp249Cys), provides a valuable molecular tool for precise diagnosis and improved clinical management in patients with diencephalic‐mesencephalic junction dysplasia syndrome.

References

• Molecular syndromology • 2024 • Many Faces of Diencephalic-Mesencephalic Junction Dysplasia Syndrome with GSX2 and PCDH12 Variants PMID:39119454
• Disease models & mechanisms • 2025 • Modelling a pathological GSX2 variant that selectively alters DNA binding reveals hypomorphic mouse brain defects PMID:39882631

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