UBR7 – Li-Campeau Syndrome

UBR7 has emerged as a strong candidate gene underlying Li-Campeau syndrome, an autosomal recessive disorder characterized by intellectual disability, global developmental delay, genital anomalies, and abnormal heart morphology. Multiple independent studies have identified biallelic pathogenic variants in UBR7 that co‐segregate with the phenotype. In one report, the eighth case of Li-Campeau syndrome was described in a Turkish patient carrying a homozygous splice site variant; the co-segregation was confirmed by Sanger sequencing in the nonconsanguineous family (PMID:36757286).

Genetic evidence across studies indicates that Li-Campeau syndrome is caused by recessive loss-of-function mutations in UBR7. For instance, one study reported a compound heterozygous state including a missense variant, c.863T>C (p.Leu288Pro), in a 7-year-old patient, while another described the homozygous splice site mutation c.1185+1G>C. Both variants disrupt highly conserved regions, with in silico analyses and segregation data supporting a pathogenic impact (PMID:37478672). This concurs with the recessive inheritance pattern and underlines the variability in the mutational spectrum of UBR7.

Functional studies further support the pathogenicity of UBR7 variants in Li-Campeau syndrome. Experimental assays have demonstrated that deleterious mutations in UBR7 impair its E3 ubiquitin-protein ligase activity, crucial for protein homeostasis. In the Turkish case, the splice site variant was linked to loss of function in a key enzymatic domain, consistent with the clinical phenotype and bioinformatic predictions (PMID:36757286).

While multiple studies provide robust genetic and functional evidence, additional cases and experimental validations have been reported that exceed the minimum ClinGen criteria, thus reinforcing the association. The discovery of recurrent and diverse variant classes across independent cohorts adds to the overall confidence in UBR7’s role in Li-Campeau syndrome.

Importantly, the integration of genetic findings, confirmed segregation, and detailed functional assays presents a coherent narrative supporting the clinical utility of UBR7 testing. This comprehensive evidence base ensures that UBR7 is a reliable biomarker not only for diagnostic decision-making but also as a potential target in future therapeutic interventions.

Key take‑home sentence: The strong, multi‑layered association between biallelic UBR7 variants and Li‑Campeau syndrome highlights its significant value in both clinical diagnostics and future therapeutic developments.

References

• American journal of medical genetics. Part A • 2023 • Eighth case of Li-Campeau syndrome in a Turkish patient caused by a novel pathogenic variant in UBR7 and expanding the phenotype PMID:36757286
• Stem cell research • 2023 • Establishment of a novel human induced pluripotent stem cell line (SIPDi001-A) with compound heterozygous mutations in the UBR7 gene from a Li‑Campeau syndrome patient PMID:37478672

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