Abstract / Summary
Abstract 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 FMR1 premutations (2.6%), chromosomal abnormalities (1.5%) and adrenal autoimmunity (1.8%). Among the 68 women with POI who underwent WGS, a likely causal genetic diagnosis was identified in 17.6% (12/68) of cases. Autosomal recessive variants were enriched among women with primary amenorrhea, whereas heterozygous or multiple rare variants in DNA damage repair pathways predominated in secondary amenorrhea. While overall mean PGS did not differ from controls, low PGS (<-0.5 SD) compounded POI risk in a subset of women carrying rare variants. Conclusions 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.