RNF125 – Tenorio syndrome

RNF125, a RING finger E3 ubiquitin ligase, has been implicated in Tenorio syndrome, a neurodevelopmental disorder characterized by intellectual disability, abnormal heart morphology, macrocephaly, and other features. Early reports identified a novel variant, c.670G>C (p.Glu224Gln), in an individual whose clinical presentation included congenital heart disease, intellectual disability, and macrocephaly (PMID:37986019). This initial observation provided a critical starting point linking RNF125 dysfunction to the disease phenotype.

Further validation emerged from a multi‑patient study that reported 14 additional cases with pathogenic missense variants in RNF125, including c.521G>T (p.Arg174Leu) and c.521G>A (p.Arg174His) (PMID:34196401). Segregation analysis within these families, despite instances of variants being inherited from apparently asymptomatic parents, revealed that subtle phenotypic findings upon deep clinical evaluation support a consistent inheritance pattern. Together, these findings underscore the clinical validity of the association.

Genetic evidence is reinforced by the demonstration that distinct missense mutations in RNF125 contribute to Tenorio syndrome. The reported variant c.670G>C (p.Glu224Gln), which disrupts the ubiquitin interaction motif, exemplifies how a single coding alteration can perturb ubiquitin chain binding without abolishing E3 ligase activity. The cumulative data—comprising at least 15 probands across independent reports (PMID:37986019 and PMID:34196401)—support a robust genetic association.

Functional studies have provided mechanistic insight by showing that the RNF125 variant impairs the capacity of the enzyme to interact with lysine 63‑linked ubiquitin chains, an interaction essential for proper RIG‑I signalling and immune regulation. This functional deficiency aligns with the patient phenotypes, reinforcing the notion that aberrant ubiquitin chain binding underlies the pathogenesis of Tenorio syndrome. The concordance between the observed functional impairment and the clinical phenotype strengthens the overall pathogenic model.

While segregation analysis noted that some variants were inherited from mildly affected or asymptomatic parents, subsequent detailed clinical evaluation clarified that these individuals could exhibit subclinical manifestations. No compelling studies were identified that dispute the association. Instead, the evidence suggests a model of autosomal dominant inheritance with variable expressivity.

In conclusion, the integration of case report data, multi‑patient genetic studies, and supportive functional evidence establishes a Strong ClinGen classification for the association between RNF125 and Tenorio syndrome. This robust and reproducible evidence base provides valuable guidance for diagnostic decision‑making, risk assessment, and the development of therapeutic strategies.

References

• Clinical genetics • 2024 • A novel RNF125 variant associated with Tenorio syndrome alters ubiquitin chain binding PMID:37986019
• Clinical genetics • 2021 • Tenorio syndrome: Description of 14 novel cases and review of the clinical and molecular features PMID:34196401

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