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A genetic etiology accounts for unexplained primary ovarian insufficiency (POI; amenorrhea with an elevated FSH level). Subjects with POI (n=291) and controls recruited for health in old age or 1000 Genomes (n=233) underwent whole exome or whole genome sequencing. Data were analyzed using a rare variant scoring method and a Bayes factor-based framework for identifying genes harboring pathogenic variants. 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). Aggregating clinical data and genetic risk with a categorical approach may expand the genetic architecture of heterozygous rare gene variants causing risk for POI.

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