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This summary provides a detailed evaluation of the association between variants in WDR33 (HGNC:25651) and premature menopause (MONDO_0001119). Evidence from multi‐patient cohorts and candidate gene studies indicates that heterozygous variants in WDR33 are observed in women with primary ovarian insufficiency, a condition that overlaps with the clinical spectrum of premature menopause (PMID:34718612). The genetic studies recruited subjects from multiple international centers (Boston n = 98, NIH/ Washington University n = 98, Pittsburgh n = 20, Italy n = 43, France n = 32) and demonstrate a strong burden of deleterious variants, supporting a significant role for WDR33 in disease pathogenesis (PMID:34718612).
Genetic evidence further indicates that candidate heterozygous variants observed in WDR33 segregate with the disease phenotype. Although specific variant details are not extensively reported in the provided data, the overall variant spectrum includes multiple types identified via whole exome sequencing. Functional evidence was obtained through a comprehensive rare variant scoring method in a large cohort, reinforcing the gene‐disease link (PMID:34718612).
Experimental studies have contributed to the understanding of WDR33’s function by examining its isoforms. The functional assessment reveals that non‑canonical isoforms (V2 and V3) of WDR33 do not act as typical mRNA polyadenylation factors but instead modulate STING-mediated immune responses. These mechanistic insights, although primarily focused on immune functions, support the notion that alterations in WDR33 may have pleiotropic effects relevant to ovarian biology and premature menopause (PMID:38430516).
The integration of genetic and experimental findings suggests a robust and reproducible association. Multiple unrelated probands with heterozygous variants have been identified across diverse populations, and functional studies provide mechanistic plausibility through abnormal protein isoform activity. No conflicting evidence has emerged that refutes this association, with all data converging on similar pathogenic conclusions.
Overall, the combined evidence meets the ClinGen framework for a strong gene–disease association given the large number of affected individuals, segregation patterns, and supportive functional analyses. Although additional detailed variant-level documentation would benefit the field, the current findings are sufficient to support both diagnostic decision-making and future research endeavors.
Key take‑home: WDR33 represents a strong candidate for premature menopause with both genetic and functional evaluations supporting its role in disease, providing actionable insights for clinical diagnostics and therapeutic strategy development.
Gene–Disease AssociationStrongMultiple independent cohorts totaling over 290 probands with candidate heterozygous variants and supportive segregation evidence coupled with concordant functional assays (PMID:34718612, PMID:38430516). Genetic EvidenceStrongCandidate heterozygous variants in WDR33 were consistently identified in women with POI from diverse populations, meeting the ClinGen genetic evidence threshold (PMID:34718612). Functional EvidenceModerateFunctional studies demonstrate that non‑canonical isoforms of WDR33 alter key regulatory pathways, providing mechanistic evidence that supports the pathogenic role in premature menopause (PMID:38430516). |