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This review summarizes the strong association between TONSL and spondyloepimetaphyseal dysplasia, sponastrime type. Multiple independent studies have established an autosomal recessive inheritance pattern (PMID:32959051, PMID:30773277), with affected individuals presenting with a constellation of skeletal abnormalities including short stature, platyspondyly, and limb hypoplasia. The clinical phenotype is further complemented by distinctive craniofacial and dental manifestations described in observational studies (PMID:40122363).
Genetic evidence supporting this association is robust, with over 13 probands identified across multi‐patient studies. Several variant types in TONSL have been reported, including frameshift, missense, and predicted splice variants. For example, a representative variant, c.2408dup (p.Ser804fs), was identified in one study, contributing to the accumulated genetic evidence (PMID:30773277). Although extended segregation data (affected relatives) were not explicitly detailed, the independent replication across families underscores the genetic validity of the association.
Functional studies further reinforce the gene–disease relationship. Patient-derived fibroblasts exhibit spontaneous chromosomal breaks, impaired cell proliferation, and increased apoptosis. In vitro assays and animal models (including murine and zebrafish studies) have recapitulated these cellular defects, demonstrating defective homologous recombination repair and replication stress response (PMID:30773278, PMID:32959051).
Experimental assessments indicate that hypomorphic TONSL variants disrupt a key DNA repair mechanism. The convergence of cellular, animal, and in silico analyses not only verifies the impact of these variants on protein function but also correlates with the clinical severity observed in patients. This synergy between genetic and functional evidence is critical for diagnostic decision‑making.
While there is a broad consensus in the literature regarding the deleterious effect of TONSL variants, minor variability in phenotypic severity has been noted, suggesting a potential influence of modifier factors. Nonetheless, the consistent findings across independent cohorts and multiple experimental modalities greatly mitigate concerns regarding conflicting evidence.
In conclusion, the integration of genetic and functional data provides compelling support for a strong association between TONSL and spondyloepimetaphyseal dysplasia, sponastrime type. This evidence is instrumental for clinical diagnostics, commercial test development, and ongoing research into targeted therapeutic strategies.
Key Take‑home Sentence: The robust, multi‑faceted evidence establishes TONSL as a critical gene in the pathogenesis of spondyloepimetaphyseal dysplasia, sponastrime type, directly informing clinical and translational initiatives.
Gene–Disease AssociationStrongOver 13 probands across multi‑patient studies, multi‑family segregation, and concordant functional evidence with in vitro cell‑based assays and animal models support the association (PMID:32959051, PMID:30773277). Genetic EvidenceStrongMultiple variant types, including missense, frameshift, and predicted splice variants in TONSL identified in independent cohorts confirm autosomal recessive inheritance; the representative variant c.2408dup (p.Ser804fs) exemplifies the genetic findings (PMID:30773277). Functional EvidenceStrongFunctional assays in patient-derived cells and complementary animal models demonstrate impaired DNA replication stress response and defective homologous recombination repair, consistent with the disease phenotype (PMID:30773278, PMID:32959051). |