Exploring genetic variants in premature ovarian insufficiency: a cohort-based investigation of monogenic etiologies

Premature ovarian insufficiency (POI), affecting about 3.5% of women under 40, is marked by menstrual irregularities, amenorrhea, and heterogeneous pubertal development. Although next-generation sequencing (NGS) has expanded the list of POI-associated genes, most cases remain unexplained, and the clinical diagnostic value of gene panels is still insufficiently assessed.

This study combines a cohort-based analysis with a critical methodological reassessment of NGS diagnostic yield in POI.

Prospective multicenter observational cohort study (2016-2023).

Three Belgian academic hospitals.

One hundred sixty unrelated women with idiopathic POI and 716 female controls.

Targeted NGS of 155 POI-associated genes. Variants were classified following American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines, and genes were evaluated using the latest gene-disease relationship (GDR) scoring framework.

Identification of pathogenic/likely pathogenic (P/LP) variants (primary outcome). Diagnostic yield of the gene panel based on genes with strong evidence (secondary outcome).

Pathogenic/likely pathogenic variants were identified in 19.3% of patients; however, only 7.5% were considered clinically relevant based on gene validity and inheritance patterns. Limiting analysis to the 40 genes with the strongest GDR evidence yielded a 4.4% diagnostic rate. Adding 10 genes supported by recent literature increased the yield to 7.5%. In patients with primary amenorrhea, the diagnostic rate reached 15.4%. These findings highlight the gap between variant burden and true diagnostic yield in POI.

Targeted NGS panels provide valuable clinical insight into POI genetics but should be complemented with broader genomic approaches for comprehensive diagnosis.