{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Obstetrics and Gynecology, Fertility Clinic, Hôpital Universitaire de Bruxelles (H.U.B), CUB Hôpital Erasme, Université Libre de Bruxelles (ULB), Brussels 1070, Belgium.",
    "Department of Human Genetics, Hôpital Universitaire de Bruxelles (H.U.B), CUB Hôpital Erasme, Université Libre de Bruxelles (ULB), Brussels 1070, Belgium.",
    "Clinical Sciences-Research Group Reproduction and Genetics, Centre for Medical Genetics, Medical Genetics, Vrije Universiteit Brussel VUB, Universitair Ziekenhuis Brussel UZ Brussel, Brussels 1090, Belgium.",
    "Clinical 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.",
    "Centre for Medical Genetics, Medical Genetics, Clinical Sciences-Research Group Reproduction and Genetics, Vrije Universiteit Brussel VUB, Universitair Ziekenhuis Brussel UZ Brussel, Brussels 1090, Belgium.",
    "Gynecology, Fundació Puigvert de Barcelona, Hospital de Sant Pau UAB, Barcelona 08025, Spain.",
    "Department of Gynecology, Centre Hospitalier Universitaire de Liège, Liège 4000, Belgium.",
    "Department of Gynecology, Hôpital Universitaire Saint-Pierre, Brussels 1000, Belgium.",
    "Human Genetics, Institute of Interdisciplinary Research in Human and Molecular Biology (IRIBHM), Université Libre de Bruxelles (ULB), Brussels 1070, Belgium."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 11,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Asma Sassi",
      "orcid": "0000-0003-0085-7824"
    },
    {
      "affs": [
        1
      ],
      "name": "Xavier Peyrassol",
      "orcid": "0009-0000-3276-1726"
    },
    {
      "affs": [
        1
      ],
      "name": "Martina Marangoni"
    },
    {
      "affs": [
        2
      ],
      "name": "Alexander Gheldof",
      "orcid": "0000-0002-8320-1961"
    },
    {
      "affs": [
        2,
        3,
        4
      ],
      "name": "Sonia Van Dooren",
      "orcid": "0000-0001-8583-1994"
    },
    {
      "affs": [
        5
      ],
      "name": "Beatrice Alvaro Mercadal"
    },
    {
      "affs": [
        6
      ],
      "name": "Axelle Pintiaux"
    },
    {
      "affs": [
        7
      ],
      "name": "Caroline Antoine"
    },
    {
      "affs": [
        8
      ],
      "name": "Marc Abramowicz"
    },
    {
      "affs": [
        1
      ],
      "name": "Julie Désir"
    },
    {
      "affs": [
        0
      ],
      "name": "Anne Delbaere"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/4hcwy90ph63jw.bib",
  "cited_by": 0,
  "doi": "10.1210/jendso/bvag215",
  "fulltext_url": "https://europepmc.org/articles/PMC13714545",
  "id": "4hcwy90ph63jw",
  "issns": [
    "2472-1972"
  ],
  "landing_url": "https://europepmc.org/article/MED/42953442",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "AcademicSubjects/MED00250"
    ],
    [
      "heading",
      "Clinical Research Article"
    ],
    [
      "heading",
      "Jes/10"
    ],
    [
      "openalex",
      "1311|Genomics and Rare Diseases"
    ]
  ],
  "openalex": "W7224100726",
  "pdf_url": "https://europepmc.org/articles/PMC13714545?pdf=render",
  "pmcid": "PMC13714545",
  "pmid": "42953442",
  "published": "2026-10-28",
  "publisher": "The Endocrine Society",
  "ris": "https://research.draconitic.com/paper/4hcwy90ph63jw.ris",
  "sources": [
    {
      "first_seen": "2026-10-31T00:20:40Z",
      "native_id": "MED:42953442",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42953442"
    },
    {
      "first_seen": "2026-11-01T12:22:01Z",
      "native_id": "PMC13714545",
      "source": "pmc",
      "url": "https://doi.org/10.1210/jendso/bvag215"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:1311|Genomics and Rare Diseases",
      "subfield": "genetics-genomics"
    }
  ],
  "title": "Exploring genetic variants in premature ovarian insufficiency: a cohort-based investigation of monogenic etiologies.",
  "title_text": "Exploring genetic variants in premature ovarian insufficiency: a cohort-based investigation of monogenic etiologies.",
  "type": "peer-reviewed",
  "updated_at": "2026-11-01T12:22:01Z",
  "url": "https://research.draconitic.com/paper/4hcwy90ph63jw",
  "venue": "Journal of the Endocrine Society",
  "versions": []
}