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Context A genetic etiology likely accounts for the majority of unexplained primary ovarian insufficiency (POI). Objective We hypothesized that heterozygous rare variants and variants in enhanced categories are associated with POI. Design The study was an observational study. Setting Subjects were recruited at academic institutions. Patients Subjects from Boston (n = 98), the National Institutes of Health and Washington University (n = 98), Pittsburgh (n = 20), Italy (n = 43), and France (n = 32) were diagnosed with POI (amenorrhea with an elevated follicle-stimulating hormone level). Controls were recruited for health in old age or were from the 1000 Genomes Project (total n = 233). Intervention We performed whole exome sequencing (WES), and data were analyzed using a rare variant scoring method and a Bayes factor-based framework for identifying genes harboring pathogenic variants. We performed functional studies on identified genes that were not previously implicated in POI in a D. melanogaster model. Main Outcome Genes with rare pathogenic variants and gene sets with increased burden of deleterious variants were identified. Results Candidate heterozygous variants were identified in known genes and genes with functional evidence. Gene sets with increased burden of deleterious alleles included the categories transcription and translation, DNA damage and repair, meiosis and cell division. Variants were found in novel genes from the enhanced categories. Functional evidence supported 7 new risk genes for POI (USP36, VCP, WDR33, PIWIL3, NPM2, LLGL1, and BOD1L1). Conclusions Candidate causative variants were identified through WES in women with POI. Aggregating clinical data and genetic risk with a categorical approach may expand the genetic architecture of heterozygous rare gene variants causing risk for POI.

Causal and Candidate Gene Variants in a Large Cohort of Women With Primary Ovarian Insufficiency