THU630 Improving Diagnostic Precision In Primary Ovarian Insufficiency Using Comprehensive Genetic And Autoantibody Testing

Abstract

Abstract Disclosure: E. Vogt: None. E. Bratland: None. S. Berland: None. A. Lund: None. B. Sigridur: None. E.S. Husebye: None. Context: Primary ovarian insufficiency (POI) affects approximately 1% of women and has life-changing consequences due to infertility and increased risk of complications related to premature estrogen deficiency. Clinical presentations and pathogenic mechanisms of POI are heterogeneous, but the underlying etiology remains unknown in the majority of cases. Improved diagnostic precision will be an important step towards tailoring future treatments in women with POI. Objective: To evaluate phenotypes and distribution of underlying etiologies in women with newly diagnosed POI. Methods: Prospective cross-sectional study of 100 women with newly diagnosed POI of unknown cause. Standard recommended diagnostic investigations were performed, including screening for chromosomal anomalies and premutations in the fragile X mental retardation 1 gene (FMR1). In addition, we used a two-tiered next generation sequencing (NGS)-based strategy, and assays of autoantibodies against steroid cell autoantigens. Results: We identified chromosomal aberrations in 8%, FMR1 premutations in 3%, genetic variants related to POI in 16%, and autoimmune POI in 3%. A homozygous pathogenic variant in the ZSWIM7 gene (NM_001042697.2) was found in two women, corroborating this as a novel cause of monogenic POI. No associations between phenotypes and genotypes were found. Conclusion: By adding an NGS-based POI-related gene panel, clinical whole exome sequencing, and specific immunoprecipitating autoantibody assays to the recommended diagnostic workup, we were able to determine a likely etiology in one third of the patients. Presentation: Thursday, June 15, 2023