Work

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

Year: 2026

Type: article

Abstract: Context: 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. Objective: This study combines a cohort-based analysis with a critical methodological reassessment of NGS diagnostic yield in POI. Design: Prospective multicenter observational cohort study (2016-2023). Setting: Three Belgian academic hospitals. Patients: One hundred sixty unrelated women with idiopathic POI and 716 female controls. Intervention: 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. Main outcome measures: Identification of pathogenic/likely pathogenic (P/LP) variants (primary outcome). Diagnostic yield of the gene panel based on genes with strong evidence (secondary outcome). Results: 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. Conclusion: Targeted NGS panels provide valuable clinical insight into POI genetics but should be complemented with broader genomic approaches for comprehensive diagnosis.

Source: Journal of the Endocrine Society

DOI: 10.1210/jendso/bvag215