USP36 and Premature Menopause

This summary evaluates the association between USP36 (HGNC:20062) and premature menopause (MONDO_0001119), a phenotype within the spectrum of primary ovarian insufficiency (POI). The evidence is derived chiefly from a large exome sequencing study recruiting women with POI from multiple academic centers in Boston, the National Institutes of Health, Washington University, Pittsburgh, Italy, and France (n = 98, 98, 20, 43, and 32 respectively [PMID:34718612]). This observational study identified candidate heterozygous rare variants in USP36 along with six other genes that have not been previously implicated in POI. The identification of these variants was supported by a categorical analysis integrating both genetic burden testing and functional evaluation.

The genetic investigations focused on women presenting with amenorrhea (HP:0000141) in the context of an elevated follicle-stimulating hormone level. Although specific segregation data for USP36 were not detailed in the report, the recurrent identification of USP36 variants in a cohort of 291 women with POI underscores its contribution to the genetic burden in this disease (PMID:34718612). The heterozygous nature of the variants further suggests an autosomal dominant mode of inheritance in this context. The study methodology included comprehensive whole exome sequencing paired with rigorous rare variant scoring and a Bayes factor-based framework to pinpoint candidate disease genes.

In parallel, functional assessment using a Drosophila melanogaster model provided experimental support for the role of USP36 in ovarian function. These studies demonstrated that perturbation of USP36 in the model organism recapitulated key aspects of the POI phenotype, thereby reinforcing the concept that disruption of USP36 function contributes to premature menopause. Although no specific coding variant meeting the full HGVS requirements (i.e. a c. description with an associated p. effect) was described in the POI study, the consistency of the genetic and experimental findings strengthens the validity of the association.

The integrated findings from both genetic and functional studies contribute to an emerging narrative where USP36 is implicated as a candidate gene for premature menopause. The evidence spans multi-center clinical data and supportive experimental insights that align with the biological plausibility of USP36 in ovarian physiology. While the absence of detailed segregation data and a specific cDNA-level variant limits the granularity of the genetic evidence, the breadth of the study cohort and the concordant functional outcomes lend moderate weight to this association.

Based on these findings, the overall gene‑disease association for USP36 with premature menopause is rated as Moderate. Genetic evidence is supported by the identification of rare heterozygous variants in a large, diverse cohort of POI patients, and functional evidence is underpinned by Drosophila model assays that mimic disease-relevant phenotypes (PMID:34718612). Additional experimental replication and segregation analyses could further refine the clinical validity of this association.

Key Take‑home sentence: The integration of multi‑center genetic data with experimental modeling supports the clinical utility of USP36 in the diagnostic evaluation of premature menopause, warranting further investigation in clinical and research settings.

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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