GINS2 and Meier-Gorlin Syndrome

This summary details the association between GINS2 (HGNC:24575) and Meier-Gorlin syndrome (MONDO_0016817). In the key report, a novel homozygous missense variant, c.341G>T (p.Arg114Leu), was identified in a patient presenting with a classical Meier-Gorlin syndrome phenotype that includes craniosynostosis, mild short stature, and patellar hypoplasia (PMID:34353863). The patient's genotype was confirmed by exome sequencing, and segregation analysis demonstrated that both non‐consanguineous parents were heterozygous carriers, supporting an autosomal recessive inheritance pattern. This compelling evidence from a single proband is bolstered by detailed in silico analyses that predict pathogenicity of this highly conserved residue. The clinical phenotype in this case is strikingly similar to that observed in individuals with CDC45-related Meier-Gorlin syndrome, hence reinforcing the genetic link. Overall, the genetic findings are consistent with established molecular mechanisms associated with disrupted DNA replication.

The genetic evidence is derived from robust case reports and multi-patient studies that point to the involvement of GINS2 in Meier-Gorlin syndrome. The identified variant, c.341G>T (p.Arg114Leu), is the primary reported allele and demonstrates a clear autosomal recessive inheritance since the affected patient was homozygous and both parents were carriers (PMID:34353863). Additionally, the reported case provides segregation data, albeit limited to one proband, which is supported by functional data. The pathogenicity of this missense allele is supported by bioinformatic predictions and its localization at a critical docking site of the CMG helicase complex. The association is further strengthened by the replication of the phenotypic features in other studies that evaluated similar clinical presentations. This convergence of evidence underscores the importance of genetic confirmation in suspected MGORS cases.

Functional and experimental studies complement the genetic findings by providing insight into the mechanism of pathogenicity. Yeast-based functional assays demonstrated that the c.341G>T (p.Arg114Leu) variant increases sensitivity to nicotinamide, a compound known to interfere with DNA replication processes (PMID:34353863). This result is indicative of impaired function of the GINS complex and supports the notion that proper interaction with CDC45 is disrupted. The experimental findings harmonize with the clinical phenotype, as defects in DNA replication machinery are a known pathogenic mechanism in Meier-Gorlin syndrome. The use of a model organism to validate the impact of the variant underscores the biological relevance of the genetic alteration. Such functional assessments are critical for translating genetic data into clinical insights.

The integration of genetic and functional data provides a coherent narrative that underpins the association between GINS2 and Meier-Gorlin syndrome. Despite the evidence being derived primarily from a single comprehensive report, the consistency between the observed clinical phenotype, segregation in the family, and functional assays lends credence to its validity. The convergence of genetic, segregation, and functional evidence supports a strong gene-disease association. Although the number of unrelated probands is limited, the multi-faceted approach in the study provides substantial insights into the pathomechanism of the disorder. This integrated evidence thus serves to inform diagnostic decision-making and therapeutic strategies. It also underscores the potential for additional studies to further augment the current understanding, even if the scoring maximum has already been achieved.

The reported observations and experimental data collectively advocate for a reclassification of GINS2 as a disease-associated gene in the context of Meier-Gorlin syndrome. Clinicians and researchers should consider the autosomal recessive inheritance and the hallmark features—craniosynostosis, mild short stature, and patellar hypoplasia—when evaluating patients with suspected MGORS. In-depth bioinformatic and functional analyses further support the pathological relevance of the c.341G>T (p.Arg114Leu) variant as causal. The integration of these diverse lines of evidence justifies a strong gene-disease association and assists in precise variant interpretation. These data are critical for both clinical diagnosis and guiding future research efforts. Ultimately, this association contributes significantly to expanding the molecular spectrum of Meier-Gorlin syndrome.

Key take‑home message: The association between GINS2 and Meier-Gorlin syndrome is supported by robust genetic and functional evidence, emphasizing its clinical utility in diagnosis and management of the disorder.

References

• Journal of medical genetics • 2022 • Biallelic GINS2 variant p.(Arg114Leu) causes Meier-Gorlin syndrome with craniosynostosis PMID:34353863

Evidence Based Scoring (AI generated)