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TUSC3 is increasingly recognized as a key gene in the etiology of autosomal recessive intellectual disability. Multiple independent studies have implicated loss‐of‐function variants in TUSC3 as causative for cognitive impairment, with evidence arising from several case reports and multi‐patient cohorts. In particular, consanguineous families have provided clear genetic segregation patterns that bolster the association, and these studies report several frameshift and truncating variants that are absent in large population databases (PMID:21513506, PMID:27148795). The clinical descriptions include a spectrum of neurodevelopmental deficits such as intellectual disability, global developmental delay, short stature, microcephaly, and delayed speech and language development. These detailed clinical features support the relevance of TUSC3 screening in patients exhibiting these symptoms. The growing body of evidence underscores a robust genotype–phenotype correlation, which is critical for diagnostic and clinical decision‑making.
Detailed genetic analyses have revealed a distinct pattern of pathogenic variants in TUSC3. For instance, a recurrent frameshift variant, c.225del (p.Lys75AsnfsTer3), has been observed in multiple unrelated probands and segregates with the intellectual disability phenotype in autosomal recessive families (PMID:27148795, PMID:25626710). This genetic evidence is further strengthened by reports from multi‐patient studies, wherein several families demonstrated similar variant patterns, thereby reaching a cumulative count of over 10 probands with supportive segregation data (PMID:32767738, PMID:25966277). Moreover, the genetic findings are consistent with the expected impact of loss‐of‐function mutations through gene disruption. The documentation of these genetic variants, including the clearly formatted c.225del (p.Lys75AsnfsTer3), enhances the clinical utility of TUSC3 testing. Overall, the genetic data provide a strong backbone to the TUSC3–intellectual disability association.
Functional studies support the role of TUSC3 in neurodevelopment and cognitive function. Experimental data have demonstrated that TUSC3 deficiency leads to an absence of functional transcript and perturbs critical N‑glycosylation processes in the endoplasmic reticulum, which are essential for normal brain development (PMID:18452889). Such mechanistic insights reveal that the pathogenicity is driven by a loss‐of‐function effect, consistent across various cell‐based and animal models. In addition, rescue experiments have indicated that re‐expression of TUSC3 can at least partially restore normal cellular function. These functional assessments, while not exceeding the ClinGen scoring maximum individually, contribute substantively to the overall evidence. As a result, combined genetic and experimental data provide a cohesive picture of TUSC3’s involvement in intellectual disability.
The autosomal recessive inheritance pattern documented in the majority of reported families further corroborates the genetic data. Segregation analysis in these studies shows that affected individuals are homozygous for the pathogenic variants while unaffected relatives are either heterozygous carriers or lack the mutation altogether. Several reports noted multiple affected siblings within single families, supporting robust intrafamilial segregation (PMID:21513506). Although a small number of studies have explored alternative phenotypes or reported genetic polymorphisms, these do not significantly detract from the primary evidence linking TUSC3 loss‐of‐function to intellectual disability. Overall, the segregation data serve as a powerful confirmatory tool in establishing the gene–disease relationship. This rigorous segregation is critical for clinicians considering TUSC3 testing in the context of suspected autosomal recessive intellectual disability.
In synthesis, the collective clinical, genetic, and functional evidence strongly supports the association between TUSC3 and intellectual disability. The consistency across independent reports—from detailed case studies to expansive multi‐patient investigations—emphasizes the pathogenic impact of loss‐of‐function variants in TUSC3. Furthermore, the experimental findings provide essential mechanistic insights, confirming that impaired N‑glycosylation is likely central to the neurodevelopmental deficits observed. Although additional evidence exists that exceeds the ClinGen scoring maximum, the curated data are sufficient to inform both diagnostic practice and potential therapeutic strategies. The convergence of clinical phenotypes, genetic segregation, and functional impairment underlines the clinical actionability of this gene–disease relationship.
Key Take‑home: TUSC3 mutations represent a robust and actionable cause of autosomal recessive intellectual disability, warranting its inclusion in diagnostic genetic testing panels to guide effective patient management.
Gene–Disease AssociationStrongMultiple independent case reports (PMID:21513506, PMID:27148795, PMID:25626710) and multi-patient studies (PMID:32767738, PMID:25966277) have identified TUSC3 mutations in over 10 probands, with clear autosomal recessive segregation. Genetic EvidenceStrongRecurrent frameshift and truncating variants, including c.225del (p.Lys75AsnfsTer3), have been observed in unrelated families with intellectual disability, demonstrating robust segregation and absence in control populations. Functional EvidenceModerateFunctional studies show absent TUSC3 transcripts and disrupted N-linked glycosylation consistent with the patient phenotype, supporting a loss-of-function mechanism (PMID:18452889). |