Oral Presentation ESA-SRB-APEG-NZSE 2022

Functional genomics for premature ovarian insufficiency: gene discoveries and patient diagnoses with clinical impact (#140)

Elena J Tucker 1 2 , Sylvie Jaillard 3 , Shabnam Bakhshalizadeh 1 2 , Katrina M Bell 1 , Daniella Hock 4 , Erica E Davis 5 , Farrid Ullah 5 , Brianna L Kline 1 , Gorjana Robevska 1 , Jocelyn van den Bergen 1 , Chloe Hanna 1 2 6 , Katie L Ayers 1 2 , Philippe Touraine 7 , Sadishkumar Kamalanathan 8 , Gary Hime 9 , David A Stroud 4 , Andrew H Sinclair 1 2
  1. MCRI, Parville, VIC, Australia
  2. Department of Paediatrics, University of Melbourne , Parkville, VIC
  3. Service de Cytogénétique et Biologie Cellulaire, , F-35033, Rennes, France, CHU Rennes, Rennes, France
  4. Bio21 Molecular Science & Biotechnology Institute, Parkville, Australia
  5. Stanley Manne Children’s Research Institute, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, USA
  6. Department of Paediatric and Adolescent Gynaecology, Royal Children’s Hospital, Melbourne, VIC, Australia
  7. Department of Endocrinology and Reproductive Medicine, AP‐HP, Paris, France
  8. Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry , India
  9. Stem cell genetics and Drosophila models of human disease Lab, University of Melbourne, Parkville , Australia

The aim of this research program is to use genomic sequence analysis to identify the genetic cause of a major form of female infertility, premature ovarian insufficiency (POI). POI is characterised by amenorrhea and elevated follicle stimulating hormone before the age of 40. It can be an isolated condition or syndromic and associated with various co-morbidities such as cancer predisposition, hearing loss, neurodegeneration or muscle weakness. 

We have studied a diverse cohort of over 100 young women with POI using whole exome sequencing, followed by gene-centric and variant-centric filtration to identify likely causative genes and variants. The role of candidate variants in POI pathology was validated using various approaches such as the study of patient cell lines, modelling in Drosophila or zebrafish and in-vitro functional assays.

This approach has led to multiple novel POI gene discoveries, such as TP63, TFAM, MRPL50, HROB, REC8, and GGPS1. These discoveries have highlighted the important role of mitochondria and meiosis for ovarian functioning. For example, we have established TFAM and MRPL50 as novel syndromic POI genes. We demonstrated disrupted mitochondria in patient cell lines, and abnormal ovarian development and function in zebrafish or Drosophila with disruption of the orthologous genes. We have also shown that genomic sequencing can alter and improve patient management and outcomes. For example, in several cases exome sequencing identified syndromic POI before its full clinical manifestation. This enabled surveillance and early intervention for associated co-morbidities, such as hearing loss, cancer or neurodegeneration.

Although not yet incorporated into clinical guidelines for the management of women with POI, our study demonstrates that genomic sequencing has the potential to enable new diagnoses and to change outcomes for women with this relatively common form of infertility, while also providing new insights into ovarian biology and pathology.