TRAIP – Seckel syndrome 9

This report describes the association between TRAIP and Seckel syndrome 9 based on prenatal evidence. Two consecutive affected pregnancies were identified with shared ultrasound findings including sloping forehead, micrognathia, ambiguous genitalia, brachycephaly, short extremities, single umbilical artery, choroid plexus cysts, and clenched hands (PMID:34235748). A bi‐allelic novel missense variant, reported as c.123A>T (p.Lys41Asn), was identified in TRAIP among these cases, implicating its role in disease causation. Given the prenatal setting and the recurrence of these anomalies in independent cases, the results support a gene-disease association, albeit with a limited sample size. The genetic evidence is primarily based on case reports with a small number of probands and no extended family segregation data. The observed phenotype is consistent with Seckel syndrome 9, a disorder under the primordial dwarfism spectrum. Overall, while the clinical evidence is limited in quantity, it highlights a potential pathogenic role of TRAIP in the etiology of Seckel syndrome 9.

The functional data available for TRAIP come from studies that have elucidated its role in regulating nuclear localization and protein stability via SUMOylation, mechanisms that are relevant to disorders of growth and development (PMID:26820530). Although these functional studies were not performed in a Seckel syndrome model per se, the mechanistic insights support the biological plausibility of TRAIP disruption contributing to primordial dwarfism phenotypes. No conflicting studies have been reported to date regarding the relationship between TRAIP and Seckel syndrome 9. Collectively, the combined clinical and experimental evidence underscores the utility of molecular confirmation in cases presenting with specific prenatal ultrasound anomalies. This integration of evidence provides a framework for diagnostic decision‑making and supports further investigation into the pathogenicity of TRAIP variants. Key take‑home: Despite the limited number of cases, TRAIP should be considered in the differential diagnosis of Seckel syndrome 9 when compatible prenatal findings are identified.

References

• Journal of clinical ultrasound : JCU • 2022 • Prenatal ultrasound diagnosis of Seckel syndrome with bi-allelic variant in TRAIP via exome sequencing PMID:34235748
• Biochemical and biophysical research communications • 2016 • SUMOylation regulates nuclear localization and stability of TRAIP/RNF206 PMID:26820530

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