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UBE3B has been robustly associated with Kaufman oculocerebrofacial syndrome, a rare developmental disorder characterized by intellectual disability, microcephaly, and generalized hypotonia. Multiple independent studies report biallelic mutations in UBE3B in patients presenting with a highly consistent clinical picture, supporting a strong gene‒disease association (PMID:23687348, PMID:31162149). The association is reinforced by genetic evidence from several unrelated probands and families where homozygous or compound heterozygous loss‑of‑function variants have been identified. Segregation analyses in consanguineous families and affected siblings further substantiate the autosomal recessive inheritance pattern of this syndrome. Functional studies demonstrate that disruption of UBE3B impairs its ubiquitin ligase activity, which in turn is correlated with abnormal neurodevelopment and growth (PMID:23200864, PMID:28003368). Additional studies have expanded the phenotypic spectrum to include various craniofacial dysmorphisms and other congenital anomalies.
Genetic evidence is strong with multiple truncating mutations (nonsense, frameshift, and splice-site variants) observed across more than 20 probands in independent reports. For instance, one recurrent variant, c.1166G>A (p.Trp389Ter), has been documented in multiple unrelated cases (PMID:23687348, PMID:29160006). The variant spectrum underscores the critical role of UBE3B’s full-length protein function in normal development. Reports of both homozygous and compound heterozygous mutations have consistently shown loss‑of‑function effects, which are mechanistically in line with the clinical manifestations observed.
Functional evidence, though not reaching the maximum scoring threshold, is compelling and supports the pathogenicity of UBE3B mutations. Cellular and animal model studies indicate that disruption of UBE3B leads to defects in protein ubiquitination, altered mitochondrial morphology, and reduced cellular proliferation. The well‐documented reduction in enzymatic function in these models parallels the clinical phenotype, thereby lending moderate support to the experimental evidence (PMID:23200864, PMID:28003368). These studies provide important biological insights into the mechanism by which UBE3B loss‐of‐function contributes to the syndrome.
In addition to genetic and experimental evidence, detailed clinical evaluations in multiple reports have revealed a consistent set of signs and symptoms including distinct craniofacial dysmorphisms, eye anomalies, and neurodevelopmental delay. The uniformity of the phenotype across diverse ethnic cohorts and geographic regions underscores the clinical utility of UBE3B genetic testing in suspected Kaufman oculocerebrofacial syndrome cases. This integrated evidence suggests that although rare, the penetrance of pathogenic UBE3B mutations is high, making it an actionable target for diagnostic decision‑making and genetic counseling.
Furthermore, while some studies have reported phenotypic overlap with other neurodevelopmental or craniofacial disorders, the aggregation of clinical data supports a distinct classification for Kaufman oculocerebrofacial syndrome. It is evident that further research might uncover additional modifiers; however, the current evidence exceeds the ClinGen scoring thresholds, fortifying the gene-disease correlation. Overall, consensus across multiple studies reinforces the clinical significance of UBE3B in driving the pathogenesis of this syndrome.
Key Take‑home: UBE3B loss‑of‑function mutations are a definitive cause of Kaufman oculocerebrofacial syndrome, making its analysis critical for accurate diagnosis, family counseling, and potential future therapeutic strategies.
Gene–Disease AssociationStrongMultiple independent studies report >20 probands and segregation in consanguineous families with homozygous or compound heterozygous loss-of-function variants in UBE3B (PMID:23687348, PMID:31162149). Genetic EvidenceStrongThe genetic evidence includes several truncating and splice-site variants across distinct cohorts and families; for example, the recurrent variant c.1166G>A (p.Trp389Ter) has been reported in multiple unrelated individuals (PMID:23687348, PMID:29160006). Functional EvidenceModerateFunctional studies demonstrate impaired ubiquitin ligase activity and altered mitochondrial dynamics upon UBE3B disruption, which parallels the observed clinical phenotype (PMID:23200864, PMID:28003368). |