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UBA7 (HGNC:12471) has emerged as a candidate gene for intellectual disability (MONDO_0001071) based on recent exome sequencing studies. Two independent investigations, one in a Finnish founder population and another in consanguineous families, have implicated UBA7 in the etiology of intellectual disability. These studies suggest that both inherited loss‑of‑function mutations and an alternate inheritance model may contribute to a pathogenic mechanism affecting neurodevelopment (PMID:33710394; PMID:28397838).
The clinical validity of the UBA7–intellectual disability association is supported by findings of novel candidate variants in multiple families. In the Finnish cohort, UBA7 was identified among three genes with an alternate inheritance pattern, whereas the consanguineous family study revealed UBA7 as one of nine autosomal recessive genes harboring loss‑of‑function variants. This cross‑cohort evidence has led to an overall clinical validity rating in the moderate range.
Genetic evidence is further underscored by the autosomal recessive inheritance reported in these studies. Although specific HGVS‐described variants for UBA7 were not provided in the variant lists, the identification of deleterious alterations in independent cohorts reinforces UBA7’s involvement. The observed mutation spectrum, primarily loss‑of‑function changes, is consistent with a disruption of gene product function that may impair neurodevelopment (PMID:28397838).
While a precise HGVS variant for UBA7 could not be extracted from the provided lists, the candidate gene designation is based on statistically significant observations in large gene discovery studies. The paucity of detailed variant-level reporting does not detract from the recurrent identification of UBA7 in robust sequencing analyses, thereby supporting its candidacy in intellectual disability etiology.
Functional studies of UBA7, derived from investigations into its role in ISGylation and protein conjugation, provide supportive but limited insight into a direct neurodevelopmental mechanism. Although UBA7 is known to activate ISG15 in antiviral and other cellular pathways, the translation of these findings to the pathogenesis of intellectual disability remains to be fully elucidated. Thus, while experimental evidence bolsters UBA7’s biological relevance, additional functional work is needed to firmly link these pathways to cognitive outcomes.
In conclusion, the integration of genetic and preliminary functional evidence suggests that UBA7 has a moderate association with intellectual disability. The convergence of findings from distinct population studies provides a compelling basis for continued research, and these data offer clinical utility by highlighting UBA7 as a candidate target for diagnostic assessment in affected individuals.
Gene–Disease AssociationModerateUBA7 was implicated as a candidate gene in two independent studies: an alternate inheritance model was observed in a Finnish founder population (PMID:33710394) and loss‑of‑function mutations were identified in consanguineous families with intellectual disability (PMID:28397838). Genetic EvidenceModerateThe identification of UBA7 among multiple autosomal recessive intellectual disability genes through loss‑of‑function variants in large-scale studies supports its genetic role, despite the absence of an individual HGVS‑described variant. Functional EvidenceLimitedFunctional studies confirm UBA7's role in ISGylation and protein conjugation, yet direct experimental evidence linking these functions to neurodevelopment and intellectual disability remains limited. |