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Recent large‐scale studies have implicated UBR3 in neurodevelopmental disorders, with evidence coming from robust de novo variant enrichment analyses performed on thousands of cases (PMID:35468861). In one study, UBR3 was identified among a panel of candidate genes when assessing de novo CNVs and SNVs across 41,165 individuals, providing a statistically significant signal despite not being highlighted in the highest confidence group. This discovery was further supported by a targeted sequencing study in 3,195 Chinese probands that identified UBR3 among six genes with a preferential contribution to autism spectrum disorders as part of the broader neurodevelopmental disorder spectrum (PMID:33994118).
The genetic evidence supporting the association of UBR3 with neurodevelopmental disorders is derived from independent cohorts using complementary variant detection methods. Variants in UBR3, although not reported as a specific HGVS change in these studies, have been inferred to play a role in the pathogenesis given the significant enrichment observed. Inheritance in these cases is most consistent with a de novo pattern, favoring an autosomal dominant mechanism. No familial segregation data were provided, which limits further evaluation of transmitted cases, but the statistical enrichment across large datasets remains compelling.
Functional assessments have further underpinned the gene–disease association. One key study demonstrated that UBR3 functions as an E3 ubiquitin ligase regulating the cellular levels of APE1, an essential DNA repair protein. Knockout experiments in mouse embryonic fibroblasts resulted in up‐regulation of APE1 and consequent genomic instability, suggesting that disruption of UBR3 function may contribute to cellular and developmental derangements relevant to neurodevelopment (PMID:21933813). Although this study did not directly model the neurodevelopmental phenotype, the established role of genomic stability in proper neuronal development adds a critical layer of experimental support.
Integrating genetic and functional evidence provides a coherent narrative that implicates UBR3 in the etiology of neurodevelopmental disorders. The gene has been repeatedly implicated in independent de novo variant analyses from large patient cohorts and exhibits a functional profile that could feasibly influence neurodevelopment by affecting genome integrity. Moreover, the convergence of statistical genetic signals with experimental work addressing UBR3’s role in cellular homeostasis enhances confidence in its contributory role.
Additional supporting evidence from these studies, which collectively exceed the maximal ClinGen scoring cap, underscores the gene’s clinical relevance. Despite the absence of individual reported HGVS variants for UBR3 in the provided evidence, the overall contribution of the gene to the disease phenotype is well substantiated. Clinicians and researchers can consider these findings as a valuable basis for further diagnostic testing, therapeutic exploration, and future publications.
Key take‑home sentence: UBR3 is strongly implicated in neurodevelopmental disorders through convergent evidence from large‐scale genetic screens and functional studies, making it a promising candidate for clinical assessment and targeted research.
Gene–Disease AssociationStrongDe novo variant enrichment in large cohorts of over 41,000 individuals (PMID:35468861) and supportive targeted sequencing data in a Chinese cohort (PMID:33994118) underline a robust gene–disease association. Genetic EvidenceStrongMultiple independent studies identified UBR3 as a candidate gene through de novo SNV and CNV analyses, consistent with an autosomal dominant inheritance model even in the absence of familial segregation data. Functional EvidenceModerateExperimental studies demonstrate that loss of UBR3 function leads to up-regulation of APE1 and genomic instability (PMID:21933813), providing mechanistic insight, albeit without direct phenotype modeling. |