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.