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This summary outlines the association between VWA8 and retinitis pigmentosa. Recent evidence from a Chinese family comprising 24 individuals has revealed heterozygous variants in VWA8, including the missense variant c.3070G>A (p.Gly1024Arg) and the nonsense variant c.4558C>T (p.Arg1520Ter). Exome sequencing of six probands (PMID:37012052) demonstrated that these variants segregate with the disease in an autosomal dominant pattern, strongly implicating VWA8 in disease causation.
Segregation analysis further supports this association, with 19 additional affected relatives showing co-segregation of the variant with the retinitis pigmentosa phenotype (PMID:37012052). This familial clustering of the phenotype adds substantial weight to the clinical validity of the observed gene–disease relationship.
Genetic evidence is reinforced by the identification of two distinct variant classes. The nonsense variant, c.4558C>T (p.Arg1520Ter), represents a loss-of-function allele, while the missense variant c.3070G>A (p.Gly1024Arg) further supports allelic heterogeneity. Both types of variants were detected in affected individuals, thereby buttressing the association between VWA8 and retinitis pigmentosa (PMID:37012052).
Functional studies provide complementary evidence. In a zebrafish knockdown model, reduced expression of VWA8 at both the mRNA and protein levels led to phenotypes that mimic the clinical presentation of retinitis pigmentosa, including severe mitochondrial damage and aberrant mitophagy activation. These experimental findings correlate well with the human phenotype and support a pathogenic mechanism involving mitochondrial dysfunction (PMID:37012052).
In summary, the integrative evidence from clinical case reports, segregation studies, and functional assessments converge to indicate a strong association between VWA8 mutations and autosomal dominant retinitis pigmentosa. Although additional independent studies could further exceed the ClinGen scoring maximum, the current body of evidence is robust for diagnostic decision‑making, commercial application, and future publication.
Key Take‑home: The convergence of strong genetic segregation and supportive functional data establishes VWA8 as a clinically actionable gene in autosomal dominant retinitis pigmentosa.
Gene–Disease AssociationStrongSix probands identified within a 24‑member autosomal dominant RP family and segregation in 19 affected relatives strongly support the gene–disease link (PMID:37012052). Genetic EvidenceStrongIdentification of both a missense and a loss‑of‑function nonsense variant, specifically c.4558C>T (p.Arg1520Ter), across multiple patients underlines robust genetic evidence (PMID:37012052). Functional EvidenceModerateZebrafish knockdown experiments demonstrating reduced VWA8 expression and mitochondrial dysfunction align with the clinical phenotype, providing moderate functional evidence for disease mechanism (PMID:37012052). |