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 details the association between VWA2 (HGNC:24709) and chronic kidney disease (MONDO_0005300). The primary evidence comes from a case study where a patient of Indian origin from a consanguineous family was found to harbor a homozygous missense variant in VWA2. This variant, c.1336C>T (p.Arg446Cys) (PMID:29351342), was identified through whole exome sequencing and homozygosity mapping and is consistent with an autosomal recessive mode of inheritance.
The genetic evidence is limited to a single proband; however, the identification of a homozygous variant in a gene with a known role in interacting with the Fraser complex provides a plausible molecular mechanism for disease. Although segregation analysis beyond the proband is not available, the molecular findings support a potential link with the clinical phenotype of chronic kidney disease.
Functional evidence further underpins the genetic findings. In vitro assays demonstrated that the c.1336C>T (p.Arg446Cys) variant results in an altered translocation dynamic of the VWA2 protein, with increased aggregation into the extracellular space. Immunohistochemical studies in a newborn mouse kidney model revealed that VWA2 co-localizes with FRAS1 in the nephrogenic zone, suggesting that the variant may disrupt normal protein interactions critical for kidney development and function (PMID:29351342).
Moreover, the experimental data indicate a dose-dependent neomorphic effect of the Arg446Cys substitution. These functional insights complement the genetic findings and further implicate VWA2 in the pathogenesis of chronic kidney disease, despite the current evidence being based on a single case report (PMID:29351342).
In summary, while the overall genetic evidence is limited by the number of probands, the integration of well-supported functional data provides a compelling rationale for the role of VWA2 in chronic kidney disease. The current findings advocate for further investigation and replication in larger cohorts to consolidate and extend these observations.
Key Take‑Home: Even with single‑case genetic evidence, functional assays demonstrating disrupted protein behavior can provide critical support for novel gene‑disease associations in chronic kidney disease.
Gene–Disease AssociationLimitedSingle proband with a homozygous missense variant identified through WES and homozygosity mapping supports the association, though additional cases are needed for a higher classification (PMID:29351342). Genetic EvidenceLimitedEvidence is derived from one affected individual with a homozygous c.1336C>T (p.Arg446Cys) variant consistent with autosomal recessive inheritance (PMID:29351342). Functional EvidenceModerateIn vitro assays and mouse immunohistochemistry demonstrate altered protein translocation and interaction with FRAS1, providing mechanistic support for the disease association (PMID:29351342). |