Abstract

   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 in SART3 in 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 the Drosophila orthologue of SART3 reveals a conserved
   role in testicular and neuronal development. Human induced pluripotent
   stem cells carrying patient variants in SART3 show disruption to
   multiple signalling pathways, upregulation of spliceosome components
   and demonstrate aberrant gonadal and neuronal differentiation in vitro.
   Collectively, these findings suggest that bi-allelic SART3 variants
   underlie a spliceosomopathy which we tentatively propose be termed
   INDYGON syndrome (Intellectual disability, Neurodevelopmental defects
   and Developmental delay with 46,XY GONadal dysgenesis). Our findings
   will enable additional diagnoses and improved outcomes for individuals
   born with this condition.

   Subject terms: Disease genetics, Genetics research, Disease model,
   Gonadal disorders, Neurodevelopmental disorders
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   The SART3 gene encodes an RNA-binding protein critical for spliceosome
   function. Here, the authors find that bi-allelic variants in SART3
   underlie a congenital condition characterised by neuro-developmental
   defects and 46,XY gonadal dysgenesis.

Introduction

   Differences of sex development (DSD) are a heterogeneous group of
   congenital conditions that affect the reproductive system^[109]1. 46,XY
   gonadal dysgenesis is a rare DSD in genetic males characterised by
   partial or complete disruption to testis development and external
   genitalia ranging from underdeveloped male to typical female (MIM
   400044, 1-9 cases per 100,000 live births^[110]2,[111]3). Causative
   genetic variants are reported in only 35–45% of 46,XY DSD
   patients^[112]4,[113]5 and a handful of genes are diagnostic for 46,XY
   gonadal dysgenesis with extragonadal comorbidities (ranging from
   neurodevelopmental defects to heart, kidney and skeletal anomalies)
   e.g. ARX (MIM 300382), ATRX (MIM 300032) DHH (MIM 605423), SOX9 (MIM
   608160) and WT1 (MIM 607102)^[114]6–[115]10. An early molecular
   diagnosis is clinically beneficial for individuals born with a DSD as
   it may inform patient clinical management in relation to adrenal and
   gonadal function, gender development and gonadal cancer
   risk^[116]11,[117]12. Importantly, since DSDs are frequently detected
   at birth, often before the emergence of comorbidities, a DSD
   presentation may trigger early genetic investigations that could result
   in diagnosis of a broader congenital syndrome. Early diagnosis permits
   timely intervention and access to disability, educational or social
   services. However, accurate genetic diagnosis of 46,XY gonadal
   dysgenesis and associated syndromes is currently hindered by
   significant gaps in our understanding of the genes and pathways
   involved.

   The spliceosome is responsible for recognising and promoting precise
   splicing of the non-coding introns in precursor messenger RNA (mRNA).
   Pathogenic variants in spliceosome components cause conditions termed
   spliceosomopathies, in which brain defects, craniofacial anomalies and
   intellectual disability are common features^[118]13. Recently,
   pathogenic variants in the TOE1 gene have been shown to cause defects
   in spliceosomal snRNA processing, leading to Pontocerebellar Hypoplasia
   Type 7 (OMIM 614969), a syndrome characterised by neurodegeneration and
   DSD including abnormalities of the gonads or external
   genitalia^[119]14. The relationship between disruption of the
   spliceosome and abnormal gonadal development is only now emerging and
   the underlying pathogenic mechanisms remain unknown.

   The squamous cell carcinoma antigen recognised by T cells 3 (SART3)
   gene, also referred to as HIV-1 Tat interacting protein of 110 kDa
   (TIP110, or p110), encodes an RNA binding protein that is critical to
   spliceosome function as it recycles small nuclear RNAs (snRNAs) during
   pre-mRNA splicing (see ref. ^[120]15 and references therein).