SPEN – Radio-Tartaglia syndrome

Radio-Tartaglia syndrome is a rare autosomal dominant neurodevelopmental disorder caused by heterozygous truncating variants in the SPEN gene. Patients present with global developmental delay, hypotonia, and characteristic facial features. Here, we integrate clinical and genetic data supporting a strong gene–disease relationship between SPEN and Radio-Tartaglia syndrome.

Genetic evidence for SPEN as the causative gene is robust. To date, 34 unrelated individuals with de novo truncating SPEN variants have been reported in association with Radio-Tartaglia syndrome (PMID:39431794). The current study describes a Japanese girl with psychomotor delay, hypotonia, hypertelorism, upslanted palpebral fissures, epicanthus folds, and a low nasal bridge in whom trio-based whole exome sequencing identified a recurrent truncating variant, c.6223_6227del (p.Ser2075GlyfsTer46) (PMID:39431794).

Clinical presentation is consistent across reports, with 100% of cases exhibiting global developmental delay and hypotonia, and a high prevalence of facial dysmorphism including hypertelorism (HP:0000316), upslanted palpebral fissures (HP:0000582), and epicanthus folds. Intellectual disability and variable feeding difficulties have also been noted, emphasizing the syndrome’s phenotypic spectrum.

All pathogenic variants identified in SPEN are predicted loss-of-function alleles clustering in the C-terminal domains, supporting haploinsufficiency as the disease mechanism. The recurrent c.6223_6227del (p.Ser2075GlyfsTer46) variant has now been observed in multiple unrelated probands, suggesting a possible mutational hotspot (PMID:39431794).

Although SPEN’s role in transcriptional repression and mRNA export is well characterized, no functional assays have directly evaluated the impact of truncating SPEN variants in patient-derived models. Thus, disease-specific functional evidence remains limited.

In summary, the accumulation of de novo truncating variants in SPEN across dozens of probands and the consistent clinical phenotype provide strong support for SPEN’s role in Radio-Tartaglia syndrome. SPEN genetic testing should be considered in patients with unexplained developmental delay, hypotonia, and characteristic facial features.

References

• American journal of medical genetics. Part A • 2025 • Clinical Features of a Japanese Girl With Radio-Tartaglia Syndrome due to a SPEN Truncating Variant. PMID:39431794

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