Prenatal Diagnosis of Radio-Tartaglia Syndrome Caused by a Loss-of-Function Variant in SPEN in a Chinese Family

Radio-Tartaglia Syndrome (RATARS) is a rare autosomal dominant neurodevelopmental disorder caused by loss-of-function (LoF) variants in SPEN. It is characterized by global developmental delay, intellectual disability, distinctive craniofacial features and multisystem involvement. To date, only a limited number of postnatal cases have been reported, and no prenatal case has been documented.

The clinical data of a 17-week pregnant woman and her affected mother who were suspected with a congenital disorder was comprehensively assessed. To investigate the genetic aetiology, whole-exome sequencing (WES) was performed to detect candidate pathogenic variants, which were subsequently validated using Sanger sequencing within the family. The proband underwent amniocentesis for prenatal genetic diagnosis of the foetus.

The 22-year-old pregnant woman presented with neurodevelopmental defects including moderate intellectual disability (ID) and hypotonia, gait abnormalities, behavioural problems, kyphosis and dysmorphic facial features. WES identified a previously unreported heterozygous frameshift variant (c.2417_2418dup, p.Arg807Aspfs*3) in the SPEN gene. Sanger sequencing confirmed the authenticity of the variant and revealed that it was inherited from the mother of the pregnant woman. Compared to the proband, the mother has a milder phenotype, mainly manifested as mild ID. Prenatal ultrasonography during pregnancy revealed no obvious structural abnormalities. However, prenatal genetic testing revealed the foetus harboured the same SPEN pathogenic variant.

This family has been diagnosed with RATARS caused by a SPEN variant. Our findings broaden the mutational and phenotypic spectrum of SPEN and characterize the first documented prenatal diagnosis of RATARS. The identification of intrafamilial phenotypic variability highlights the heterogeneous expressivity of RATARS, even among carriers of identical variants.