Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
This summary outlines the strong association between VWA1 and neuromuscular disease. Multiple independent studies have identified bi-allelic loss‐of‑function variants in VWA1 in patients presenting with a neuromyopathic phenotype. In a seminal study, six different truncating variants were found in 15 affected individuals from six unrelated families (PMID:33459760). Segregation analysis in these families further strengthens the link, with several additional affected relatives exhibiting concordant genotype‐phenotype correlations.
The genetic evidence highlights an autosomal recessive inheritance pattern. Case reports and multi‐patient series consistently report truncating variants—including the example variant c.94C>T (p.Arg32Ter)—across diverse populations. This uniformity of mutation type underscores a loss‐of‐function mechanism that is central to the pathophysiology of the disorder (PMID:33459760).
Moreover, detailed genetic analyses have been complemented by functional studies. Experimental models, such as the vwa1 knockout zebrafish, demonstrated impaired cellular processes and aberrant expression of key developmental markers, indicating that VWA1 plays a critical role in neuromuscular function. In parallel, proteomic assessments in patient‐derived samples have identified biomarker signatures that are pathophysiologically relevant to neuromyopathy (PMID:37107596, PMID:38652110).
The convergence of both genetic and functional evidence provides a coherent narrative: loss‐of‑function variants in VWA1 compromise extracellular matrix interactions in muscle and peripheral nerve tissue. This disruption likely leads to the combined neurogenic and myopathic pathology observed in patients. Functional assays further demonstrate that deficient VWA1 activity impairs key signaling pathways, consistent with the clinical presentation of muscle weakness without overt sensory deficits.
While additional studies have explored the role of VWA1 in other clinical contexts, such as craniofacial anomalies, the data pertaining to neuromuscular disease are robust and consistent. The sophisticated experimental designs—ranging from animal models to proteomic biomarker discovery—support a moderate level of functional evidence, thereby reinforcing the clinical validity of the gene‐disease association.
Key take‑home sentence: The strong genetic and moderate functional evidence for VWA1 underscores its clinical utility in diagnosing neuromuscular disease and highlights its potential as a target for future biomarker‐driven therapeutic strategies.
Gene–Disease AssociationStrongSix truncating variants identified in 15 affected individuals from six unrelated families (PMID:33459760) support a robust gene-disease association. Genetic EvidenceStrongMultiple case series and comprehensive segregation analyses, including the recurrent variant c.94C>T (p.Arg32Ter), provide strong genetic evidence for a recessive disorder. Functional EvidenceModerateFunctional studies in vwa1 knockout zebrafish and proteomic biomarker analyses in patient-derived samples demonstrate a loss-of-function mechanism consistent with the neuromuscular phenotype (PMID:37107596, PMID:38652110). |