SGSM3 – Intellectual Disability

SGSM3 is emerging as a strong candidate gene associated with nonsyndromic intellectual disability. Multiple case reports have demonstrated that patients harbor bi-allelic loss‑of‑function variants, with studies reporting a homozygous stop‑gain mutation in affected siblings. In one study, two unrelated families presented with intellectual disability and short stature, supporting autosomal recessive inheritance (PMID:39390489). The clinical findings in these families include clear evidence of segregation, with affected siblings in one family sharing the same variant. This consistent presentation across distinct populations reinforces the genetic basis of the disease association. The clinical data provide a compelling narrative for the role of SGSM3 in neurodevelopment.

The genetic evidence is anchored by the identification of a novel stop‑gain variant, c.1576C>T (p.Arg526Ter), which has been observed in affected individuals. This particular variant was reported in the abstract and serves as a representative example of the pathogenic variants detected in the gene. Autosomal recessive inheritance is strongly supported by the homozygous nature of the variant in the affected siblings, with no reports of heterozygous carriers exhibiting the phenotype. The robust demonstration of loss‑of‑function mechanisms through genetic testing is crucial for diagnostic workflows. The reported cases have undergone detailed molecular characterization which further substantiates these findings. Overall, the genetic data convincingly support the association of SGSM3 with intellectual disability (PMID:39390489).

In addition to the clear genetic findings, segregation analysis within affected families adds to the strength of the association. The evidence indicates that the variant segregates with the clinical phenotype within the pedigree, where the presence of the homozygous mutation correlates with the affected status. Although the total number of additional affected relatives with segregating variants is modest, the recurrence of the phenotype in multiple families provides additional weight to the claim. The observed segregation enhances confidence in the causative role of SGSM3 loss‑of‑function in nonsyndromic intellectual disability. Consistency among multiple case reports and familial analyses supports the pathogenicity of the variant. Thus, the familial segregation data are an integral component of the overall evidence package.

Functional studies have provided supportive, albeit limited, evidence for the gene’s involvement in neurodevelopment. Expression analyses in mouse and human tissues show that SGSM genes, including SGSM3, are highly expressed in the brain during key developmental stages. This expression pattern is consistent with a role in neural development and cognitive function. However, direct functional assays demonstrating the specific pathogenic mechanisms remain to be performed. Future in‑depth studies are needed to elucidate the exact signaling pathways affected by SGSM3 variants and how these contribute to the observed phenotype. Despite the current gap in functional validation, the expression data serve to complement the genetic evidence. This integrated evidence further supports the association between SGSM3 and intellectual disability (PMID:39390489).

Notably, while additional studies have assessed SGSM3 in the context of other disorders such as schwannomatosis, no conflicting evidence has been reported regarding its association with intellectual disability. The available data remain consistent with a model of autosomal recessive inheritance for intellectual disability, with a clear genotype–phenotype correlation. The segregation of the variant in affected families and its recurrence across different populations reduce the likelihood that the observed association is incidental. Moreover, the potential involvement of SGSM3 in diverse pathways does not diminish its role in neurodevelopment. This convergence of genetic and preliminary functional findings supports its clinical relevance. No substantial evidence has been presented that disputes the role of SGSM3 in intellectual disability.

In summary, the association between SGSM3 and nonsyndromic intellectual disability is well supported by genetic evidence, with compelling case reports and familial segregation data underlining its pathogenic potential. Although direct functional studies are limited, supporting expression data in brain tissues provide additional context. With autosomal recessive inheritance clearly demonstrated and a representative loss‑of‑function mutation (c.1576C>T (p.Arg526Ter)) identified in affected individuals, SGSM3 represents a robust candidate for diagnostic consideration. This evidence underscores its clinical utility in facilitating accurate genetic diagnosis and informing patient management. Clinicians should consider SGSM3 in the molecular workup of intellectual disability cases, as its identification can drive targeted management and counseling.

References

• Clinical genetics | 2025 | A Strong Candidate Gene for Nonsyndromic Intellectual Disability Phenotype: SGSM3. PMID:39390489

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