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Peer-reviewedCC BYJournal of the Endocrine Society

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

  • Asma Sassi1
  • Xavier Peyrassol2
  • Martina Marangoni2
  • Alexander Gheldof3
  • Sonia Van Dooren3,4,5
  • Beatrice Alvaro Mercadal6
  • Axelle Pintiaux7
  • Caroline Antoine8
  • Marc Abramowicz9
  • Julie Désir2
  • Anne Delbaere1
9 affiliations
  1. 1Department of Obstetrics and Gynecology, Fertility Clinic, Hôpital Universitaire de Bruxelles (H.U.B), CUB Hôpital Erasme, Université Libre de Bruxelles (ULB), Brussels 1070, Belgium.
  2. 2Department of Human Genetics, Hôpital Universitaire de Bruxelles (H.U.B), CUB Hôpital Erasme, Université Libre de Bruxelles (ULB), Brussels 1070, Belgium.
  3. 3Clinical Sciences-Research Group Reproduction and Genetics, Centre for Medical Genetics, Medical Genetics, Vrije Universiteit Brussel VUB, Universitair Ziekenhuis Brussel UZ Brussel, Brussels 1090, Belgium.
  4. 4Clinical Sciences-Research Group Reproduction and Genetics, Brussels Interuniversity Genomics High Throughput Core (BRIGHTcore), Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel UZ Brussel, Brussels 1090, Belgium.
  5. 5Centre for Medical Genetics, Medical Genetics, Clinical Sciences-Research Group Reproduction and Genetics, Vrije Universiteit Brussel VUB, Universitair Ziekenhuis Brussel UZ Brussel, Brussels 1090, Belgium.
  6. 6Gynecology, Fundació Puigvert de Barcelona, Hospital de Sant Pau UAB, Barcelona 08025, Spain.
  7. 7Department of Gynecology, Centre Hospitalier Universitaire de Liège, Liège 4000, Belgium.
  8. 8Department of Gynecology, Hôpital Universitaire Saint-Pierre, Brussels 1000, Belgium.
  9. 9Human Genetics, Institute of Interdisciplinary Research in Human and Molecular Biology (IRIBHM), Université Libre de Bruxelles (ULB), Brussels 1070, Belgium.
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Abstract

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.

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Cite

BibTeXRIS
BibTeX
@article{sassi2026exploring,
  title = {{Exploring genetic variants in premature ovarian insufficiency: a cohort-based investigation of monogenic etiologies.}},
  author = {Asma Sassi and Xavier Peyrassol and Martina Marangoni and Alexander Gheldof and Sonia Van Dooren and Beatrice Alvaro Mercadal and Axelle Pintiaux and Caroline Antoine and Marc Abramowicz and Julie Désir and Anne Delbaere},
  journal = {Journal of the Endocrine Society},
  year = {2026},
  month = oct,
  doi = {10.1210/jendso/bvag215},
  url = {https://europepmc.org/article/MED/42953442},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Exploring genetic variants in premature ovarian insufficiency: a cohort-based investigation of monogenic etiologies.
AU  - Asma Sassi
AU  - Xavier Peyrassol
AU  - Martina Marangoni
AU  - Alexander Gheldof
AU  - Sonia Van Dooren
AU  - Beatrice Alvaro Mercadal
AU  - Axelle Pintiaux
AU  - Caroline Antoine
AU  - Marc Abramowicz
AU  - Julie Désir
AU  - Anne Delbaere
PY  - 2026
DA  - 2026/10/28
JO  - Journal of the Endocrine Society
DO  - 10.1210/jendso/bvag215
UR  - https://europepmc.org/article/MED/42953442
AB  - 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.
SN  - 2472-1972
ER  -