Towards a greater understanding of clinical diagnostic yield in premature ovarian insufficiency: A systematic review and original cohort. — ASN Events
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Towards a greater understanding of clinical diagnostic yield in premature ovarian insufficiency: A systematic review and original cohort. (#493)

Jaidah Fergus-Mackie 1 2 , Brianna L Kline 1 2 , Svenja Pachernegg 2 , Wayne Crismani 3 4 , Katrina M Bell 2 , Sylvie Jaillard 5 6 , Katie L Ayers 1 2 , Andrew H Sinclair 1 2 , Elena J Tucker 1 2
  1. Department of Paediatrics , University of Melbourne, Melbourne, VIC, Australia
  2. Murdoch Children's Research Institute, Parkville, VIC, Australia
  3. DNA Repair and Recombination Laboratory, St. Vincent’s Institute of Medical Research, Fitzroy, VIC, Australia
  4. The Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC, Australia
  5. CHU Rennes, INSERM, EHESP, IRSET (Institut de recherche en santé, environnement et travail) - UMR_S 1085, F-35000, Univ Rennes, Rennes, France
  6. Service de Cytogénétique et Biologie Cellulaire, F-35033, Rennes, France

Background: Premature ovarian insufficiency (POI) is characterised by loss of ovarian function before age 40, affecting up to 4% of women. The condition is genetically heterogeneous, with over 100 genes implicated. Reported diagnostic yields from whole exome sequencing in POI vary considerably (5%-73%), reflecting not only differences in study cohort and design, but a fundamental conflation of research-oriented variant discovery with clinical diagnostic yield – the latter defined by pathogenic or likely pathogenic variants in high-confidence genes where identified variant(s) plausibly account for the patient’s condition. This distinction is essential for honest reporting and patient counselling.

Methods: A clinically stringent variant analysis pipeline was constructed, incorporating ACMG/AMP classification, inheritance pattern concordance assessment, and restriction to a curated panel of 88 diagnostic-grade POI genes derived from published POI gene panels and literature review. We conducted a systematic review of POI cohort studies reporting diagnostic yields from next-generation sequencing, identifying 26 studies for inclusion; all reported variants were processed through this pipeline. In parallel, whole exome sequencing was performed on a cohort of 211 individuals with POI and analysed under the same framework.

Results: The systematic review identified 26 studies encompassing 3753 individuals. Analysis of 1801 reported variants through the clinically stringent pipeline indicated a pooled diagnostic yield of 4.1%. In our independent cohort, diagnostic variants were identified in 15.2% of individuals.

Conclusion: When assessed using a standardised, clinical-grade classification pipeline, the diagnostic yield of NGS in POI is substantially lower than published rates suggest. This discrepancy reflects widespread conflation of research variant discovery with clinical diagnostic yield. Frameworks incorporating ACMG/AMP classification, validated gene lists, and inheritance pattern assessment are necessary for accurate benchmarking and clinical translation. Most POI cases with a suspected genetic cause remain unresolved with current technology – a reality that must be communicated transparently to patients.