Chromosomal and genetic causes of primary ovarian insufficiency in the Utah population.

Background: Primary ovarian insufficiency (POI) is a heterogeneous disorder, with the relative frequency of known etiologies incompletely defined at a population level. Objectives: We used chart review and whole-genome sequencing (WGS) to determine known diagnoses, pathogenic variants, and common polygenic risk. Methods: Women with POI were identified using International Classification of Diseases codes. Established clinical etiologies were documented. A subset of 68 women without an identified cause underwent WGS. Rare pathogenic variants were identified using an electronic clinical decision support framework, and common genetic risk was quantified using a polygenic risk score (PGS) for age at natural menopause. Results: Of 899 women with POI, 289 carried a diagnosis of Turner syndrome (32.1%). Of the other 610 evaluable women, established clinical etiologies were identified in 8.1%, including Conclusion: The population-level data supports rates of established POI etiologies and a gradation of genetic burden in which chromosomal abnormalities and recessive inheritance contribute to POI manifesting as primary amenorrhea, whereas heterozygous rare variants and common polygenic risk can predispose to secondary amenorrhea.