Squamous cell carcinoma antigen recognized by T cells 3 (SART3) is an RNA-binding protein with numerous biological functions including recycling small nuclear RNAs to the spliceosome. Here, we identify recessive variants inSART3in nine individuals presenting with intellectual disability, global developmental delay and a subset of brain anomalies, together with gonadal dysgenesis in 46,XY individuals. Knockdown of theDrosophilaorthologue ofSART3reveals a conserved role in testicular and neuronal development. Human induced pluripotent stem cells carrying patient variants inSART3show disruption to multiple signalling pathways, upregulation of spliceosome components and demonstrate aberrant gonadal and neuronal differentiation in vitro. Collectively, these findings suggest that bi-allelicSART3variants underlie a spliceosomopathy which we tentatively propose be termed INDYGON syndrome (Intellectual disability,Neurodevelopmental defects andDevelopmental delay with 46,XYGONadal dysgenesis). Our findings will enable additional diagnoses and improved outcomes for individuals born with this condition.