VWA8 – Systemic Lupus Erythematosus

This summary evaluates the association between VWA8 (HGNC:29071) and systemic lupus erythematosus (MONDO:0007915). The available evidence is derived predominantly from candidate gene studies conducted in familial autoimmunity cohorts. In one multi‐patient study of 31 families with overlapping autoimmune diseases, VWA8 was highlighted among a panel of T cell receptor signaling pathway genes potentially linked to systemic lupus erythematosus (PMID:31848144). However, no VWA8-specific segregation count or independent replication has been reported for this phenotype.

Genetic evidence for VWA8 in lupus is therefore limited. Although heterozygous rare variants were identified in the broader context of immune‐related genes, the candidate status of VWA8 in these studies is based on nominal co-aggregation rather than robust segregation or multiple unrelated probands (fewer than 31 families overall; PMID:31848144). This insufficiency places the gene–disease association in the limited ClinGen category.

The inheritance pattern in the familial autoimmunity study appears consistent with an autosomal dominant effect of heterozygous variants, although the complex nature of systemic lupus erythematosus may also involve additional genetic or environmental modifiers. No detailed segregation analysis specifying the number of additional affected relatives was provided for VWA8, which further limits the genetic evidence.

From the genetic standpoint, no VWA8 variant unique to lupus has been explicitly reported in these studies. For completeness, we note that a truncating variant, c.4558C>T (p.Arg1520Ter), has been documented in VWA8 in a functional assessment setting; however, that study linked VWA8 to retinitis pigmentosa (MONDO:0019200) rather than systemic lupus erythematosus (PMID:37012052). The overlap of VWA8 in disparate disease contexts further complicates the evaluation of its role in lupus.

Functional studies for VWA8 have provided compelling evidence for its role in retinal pathology through loss-of-function mechanisms and aberrant mitochondrial regulation. In contrast, no functional or mechanistic investigations directly support its involvement in systemic lupus erythematosus. The dichotomy between the functional data in retinitis pigmentosa and the candidate gene evidence in familial autoimmunity underscores the need for disease-specific experimental validation.

Overall, while VWA8 emerges as a candidate in genomic screens of familial autoimmunity, the association with systemic lupus erythematosus remains limited due to the lack of robust segregation, replication, and direct functional support. Key take‑home: clinicians and researchers should consider VWA8 a provisional candidate for lupus, warranting further functional studies and larger cohort analyses before routine clinical application.

References

• Annals of the rheumatic diseases • 2020 • Germline genetic patterns underlying familial rheumatoid arthritis, systemic lupus erythematosus and primary Sjögren's syndrome highlight T cell-initiated autoimmunity PMID:31848144
• Journal of medical genetics • 2023 • Mutations in VWA8 cause autosomal-dominant retinitis pigmentosa via aberrant mitophagy activation PMID:37012052

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