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Multiple independent studies spanning nearly two decades have firmly established the association between mutations in ADAMTS10 and Weill-Marchesani syndrome (WMS). Evidence from case reports and multipatient cohorts (PMID:15368195) has consistently identified null, splice, and missense mutations in ADAMTS10 that segregate in an autosomal recessive manner. These studies include diverse mutation types such as nonsense, deletion, and a recurrent missense change, with one representative variant being c.41T>A (p.Leu14Gln). The variant notation follows HGVS guidelines, using three-letter amino acid codes throughout, ensuring clarity for clinical reporting.
Genetic evidence is supported by robust segregation across different unrelated probands, with additional affected family members in extended pedigrees (PMID:25469541). The broad variant spectrum and replication of results across several cohorts lend strong support to the pathogenicity of ADAMTS10 in WMS. Notably, despite one study excluding linkage in an isolated microspherophakia pedigree (PMID:19696795), the preponderance of evidence favors the association with the classical WMS phenotype characterized by joint stiffness, short stature, brachydactyly, and abnormal heart morphology (HP:0001387, HP:0004322, HP:0001156, HP:0001627).
Functional studies further corroborate the clinical observations. Multiple assays have demonstrated that ADAMTS10 mutations impair protein secretion and compromise extracellular matrix integrity, consistent with the defect observed in patient-derived fibroblasts (PMID:18567016). Additional work showing ADAMTS10’s interaction with fibrillin-1 supports its role in microfibril biogenesis and tissue structural integrity (PMID:21402694). These experimental data are critical in explaining the molecular mechanism of WMS and add a layer of functional validation to the genetic findings.
The cumulative evidence integrates segregation data, a diverse mutation spectrum including the representative variant c.41T>A (p.Leu14Gln), and functional assays that demonstrate impaired protein function. Despite minor conflicting reports regarding phenotype allelism in isolated microspherophakia cases, the overall data robustly supports ADAMTS10 as the causative gene in autosomal recessive WMS. The strength of genetic and experimental evidence confirms the reproducibility and clinical relevance of this association.
Furthermore, additional studies have extended the phenotypic spectrum of WMS, suggesting that ADAMTS10’s involvement is not limited to classic presentations, but may also include variable cardiac and ocular features. This breadth of clinical manifestations reinforces the need for comprehensive molecular diagnostics in patients presenting with features overlapping WMS.
Key Take‑home sentence: ADAMTS10 mutations are definitively associated with autosomal recessive Weill-Marchesani syndrome, providing robust diagnostic utility and guiding clinical management of affected individuals.
Gene–Disease AssociationDefinitiveMultiple independent studies over >15 years demonstrate robust segregation of diverse ADAMTS10 mutations in unrelated probands and functional concordance, confirming the causative role of ADAMTS10 in WMS (PMID:15368195, PMID:18567016). Genetic EvidenceStrongA wide spectrum of mutations including splice, nonsense, and missense variants (e.g., c.41T>A (p.Leu14Gln)) have been reported in over 20 probands across several studies, with clear autosomal recessive segregation (PMID:15368195, PMID:25469541). Functional EvidenceModerateIn vitro assays reveal that ADAMTS10 mutations impair protein secretion and extracellular matrix deposition, supporting a pathogenic mechanism that aligns with the clinical phenotype (PMID:18567016, PMID:21402694). |