Oral Presentation ESA-SRB 2023 in conjunction with ENSA

Multiomics for premature ovarian insufficiency: gene discoveries and clinical impact (#2)

Elena Tucker 1 2 , Sylvie Jaillard 3 4 , Shabnam Bakhshalizadeh 1 2 , Katrina M Bell 1 , Daniella H Hock 5 , Gorjana Robevska 1 , Jocelyn van den Bergen 1 , Brianna L Kline 1 , Katie L Ayers 1 2 , Philippe Touraine 6 , Chloe Hanna 1 7 , Sonia R Grover 7 , Gary R Hime 8 , David A Stroud 1 5 9 , Andrew H Sinclair 1 2 9
  1. Murdoch Children's Research Institute, Melbourne, Australia
  2. Department of Paediatrics, University of Melbourne, Melbourne, Australia
  3. Univ Rennes, CHU Rennes, INSERM, EHESP, IRSET (Institut de recherche en santé, environnement et travail), Rennes, France
  4. CHU Rennes, Service de Cytogénétique et Biologie Cellulaire, Rennes, France
  5. Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Parkville, Australia
  6. Department of Endocrinology and Reproductive Medicine, AP‐HP, Sorbonne University Medicine, Centre de Référence des Maladies Endocriniennes Rares de la Croissance et du Développement, Centre des Pathologies Gynécologiques Rares, Paris, France
  7. Department of Paediatric and Adolescent Gynaecology, Royal Children’s Hospital, Melbourne, VIC, Australia
  8. Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Australia
  9. Victorian Clinical Genetics Services, Royal Children’s Hospital, Parkville, Australia

Although genomic testing for many genetic disorders has become part of routine clinical care, this has not occurred for the management of female infertility, including premature ovarian insufficiency (POI). POI is a leading form of female infertility affecting up to 4% of women under the age of 40 and characterized by amenorrhea and elevated gonadotropins.

We have studied a diverse cohort of over 150 girls/women with POI using whole exome sequencing, identifying cause in >30%. We have validated causation using various approaches such as proteomic/transcriptomic analysis of patient cells, modelling in Drosophila or zebrafish and in-vitro functional assays. Our approach has led to multiple novel POI gene discoveries, such as TP63, TFAM, MRPL50, HROB, REC8, GGPS1 and more.

Importantly, we have shown that genomic sequencing can alter and improve patient management and outcomes. For example, we identified causative variants in NBN, EIF2B2 and LARS2 in three different patients presenting with apparently “isolated” POI. These genes are usually associated with syndromic POI in the context of cancer predisposition, neurodegeneration and hearing loss respectively. In each case genomic sequencing identified syndromic POI before its full clinical manifestation. This enabled early intervention for associated co-morbidities, with the potential to improve patient outcomes.

Although genomic testing for infertility conditions such as POI has clinical utility, the fact that many causative genes have pleiotropic roles means that genetic diagnoses can have broad and unanticipated implications for patient health. Genomic counselling plays a critical role in the implementation of genomic testing for infertility to optimize health outcomes.