Oral Presentation ESA-SRB 2023 in conjunction with ENSA

Variants in SART3 underlie a syndromic condition with gonadal dysgenesis (#25)

Katie Ayers 1 , Stefanie Eggers 2 , Ben Rollo 3 , Nadia Davidson 4 , Nicole Siddall 5 , Liang Zhao 6 , Josephine Bowles 7 , Katherine Smith 8 , Karin Weiss 9 , Ginevra Zanni 10 , Lydie Burglen 11 , Shay Ben Shachar 12 , Jenny Rosensaft 13 , Annick Rothschild 14 , Anne Jorgensen 15 , Ralf Schittenhelm 16 , Cheng Huang 16 , Gorjana Robevska 1 , Jocelyn van den Bergen 1 , Franca Casagranda 5 , Justyna Cyza 1 , Svenja Pachernegg 1 , David Wright 3 , Melanie Bahlo 4 , Alicia Oshlack 17 , Terrence O'Brien 3 , Patrick Kwan 3 , Peter Koopman 6 , Gary Hime 5 , Nadine Girard 5 , Chen Hoffmann 18 , Yuval Shilon 19 , Amnon Zung 19 , Enrico Bertini 10 , Mathieu Milh 20 , Bochra Ben Rhouma 21 , Neila Belguith 22 , Anu Bashamboo 23 , Kenneth McElreavey 23 , Ehud Banne 13 , Naomi Weintrob 18 , Bruria Ben Zeev 24 , Andrew Sinclair 1
  1. Murdoch Childrens Research Institute, Parkville, Vic, Australia
  2. Victorian Clinical Genetics Services, Melbourne, Australia
  3. Department of Neuroscience, Central Clinical School, Monash University, Alfred Centre, Melbourne, Vic, Australia
  4. Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
  5. Department of Anatomy and Neuroscience, The University of Melbourne, Melbourne
  6. Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia
  7. The University of Queensland, Brisbane, Australia
  8. AstraZeneca, Cambridge, UK
  9. The genetics institute Rambam Health Care Campus, The Ruth and Bruce Rappaport Faculty of Medicine, , Technion-Israel Institute of Technology, , Haifa, Israel
  10. Bambino Gesù Children's Hospital, IRCCS, , Rome, Italy
  11. Centre de référence des malformations et maladies congénitales du cervelet, Et Laboratoire de Neurogénétique moléculaire, Département de génétique et embryologie médicale, APHP., Sorbonne Université, Hôpital Trousseau, , Paris, France
  12. Tel-aviv Sourasky Medical Center, Tel-aviv, Israel
  13. Genetics Institute, Kaplan Medical Center, Hebrew University Hadassah Medical School, Rehovot, Israel
  14. Edmond and Lily Safra Children's Hospital, Chaim Sheba Medical Center, Ramat Gan, Israel
  15. Department of Growth and Reproduction, Copenhagen University Hospital, Denmark
  16. Monash Proteomics & Metabolomics Facility, Biomedicine Discovery Institute, Department of Biochemistry and Molecular Biology, , Monash University, Clayton, Australia
  17. Peter Maccallum Cancer Center, Melbourne, VIC
  18. Sackler school of Medicine, Tel-Aviv University, Israel
  19. Kaplan Medical Center, , Hebrew University Hadassah Medical School, Rehovot, Israel
  20. Department of Neuroradiology. Timone Hospital. , Aix-Marseille Univ. APHM, Marseille, France
  21. Higher Institute of Nursing Sciences of Gabes, University of Gabes, Gabes, Tunisia
  22.  Laboratory of Human Molecular Genetics, Faculty of Medicine of Sfax, Sfax University, Sfax, Tunisia
  23. L’institut Pasteur, Paris, France
  24. Sheba Medical Center, Tel Aviv, Israel

Differences of sex development (DSD) represent a major paediatric concern and can be associated with >200 congenital conditions. Clinical management of these conditions is challenging but can be guided by a genetic diagnosis to improve patient health and wellbeing. 

Our group employs genomic sequencing of DNA from undiagnosed patients with syndromic DSD to find novel genetic causes. Recently we have identified recessive variants in the Squamous cell carcinoma antigen recognized by T cells 3 (SART3) gene in nine individuals from six families. All affected individuals have intellectual disability, global developmental delay and a subset of brain anomalies. 46,XY children have gonadal dysgenesis (and have female or under-virilised male sex characteristics) whereas 46,XX children appear to have functional ovaries.

SART3 is an RNA-binding protein with numerous biological functions including recycling small nuclear RNAs to the spliceosome. SART3 is highly conserved across species. To test a role for SART3 in gonadal development, we carried out knockdown experiments of the Drosophila orthologue rnp4f. This revealed a conserved role in embryonic neuronal development, and also disrupted testis but not ovarian function, consistent with patient findings. To test pathogenicity of the patient SART3 variants we introduced these into human induced pluripotent stem cells (iPSCs). Variant iPSCs showed significant disruption of multiple signalling pathways and upregulation of spliceosome components. Using our recently developed stem cell-derived model of the gonad, we found that variant iPSCs had aberrant differentiation into gonadal cells and disruption to key testis signalling components. iPSCs also had disrupted differentiation into neuronal cells in vitro.

Collectively, these findings suggest that bi-allelic variants in SART3 underlie a new syndromic DSD. We hope these findings will enable additional diagnoses and improve outcomes for individuals with syndromic differences of sex development.