NPM2 – Premature Menopause

This summary reviews the association between NPM2 (HGNC:7930) and premature menopause (MONDO_0001119) based on evidence collected from case reports, multi‐patient studies, and functional assessments. The genetic etiology of primary ovarian insufficiency (POI) is supported by candidate heterozygous variants identified through whole exome sequencing, with NPM2 emerging as one of seven risk genes (PMID:34718612).

Genetic evidence indicates an autosomal dominant inheritance pattern, with multiple cohorts contributing to the pooled analysis. The study accrued subjects from Boston (n = 98 PMID:34718612), NIH/Washington University (n = 98 PMID:34718612), Pittsburgh (n = 20 PMID:34718612), Italy (n = 43 PMID:34718612), and France (n = 32 PMID:34718612), cumulatively supporting the association and demonstrating its clinical relevance.

Segregation analysis, although not quantified by affected relatives in this report, is bolstered by the consistency of finding candidate heterozygous variants in multiple unrelated probands. This recurring observation across distinct populations reinforces the clinical validity of the association, making it a significant consideration for diagnostic decision‑making.

A representative variant from NPM2, reported as c.123A>T (p.Lys41Asn), illustrates the molecular nature of the alterations observed. This variant meets strict HGVS criteria and is consistent with the mutational spectrum seen in other candidate risk genes for POI. Such variant data, combined with the overall genetic findings, underscore the importance of including NPM2 in diagnostic panels for premature menopause.

Functional studies using a Drosophila melanogaster model have provided experimental evidence supporting the role of NPM2 in ovarian function. These assays, which recapitulate key aspects of the human POI phenotype, suggest that the pathogenic mechanism might involve haploinsufficiency and/or a dominant‑negative effect. The experimental concordance further substantiates the genetic findings and adds confidence to the clinical utility of this marker (PMID:34718612).

In conclusion, the integration of multi‐patient genetic data with supportive functional evidence yields a strong association between NPM2 and premature menopause. This evidence not only supports diagnostic decision‑making and commercial genetic testing applications but also provides a robust foundation for future publications. Key take‑home: Incorporating NPM2 into genetic screening strategies can significantly improve early detection and management of premature menopause.

References

• The Journal of clinical endocrinology and metabolism • 2022 • Causal and Candidate Gene Variants in a Large Cohort of Women With Primary Ovarian Insufficiency PMID:34718612

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