UBE4A – Intellectual Disability

Multiple lines of evidence support a strong association between biallelic loss‐of‑function variants in UBE4A and intellectual disability. In a multi‐patient study, eight affected individuals from four unrelated families were identified as carrying biallelic UBE4A loss‐of‐function variants, including the truncating variant c.631C>T (p.Arg211Ter) (PMID:33420346). These individuals presented with a consistent syndromic phenotype, characterized by intellectual disability, global developmental delay, short stature, seizures, and hypotonia. Such recurrent findings across independent families provide compelling genetic evidence supporting the gene‑disease association.

Additional support stems from case series data where UBE4A variants, including c.384G>A (p.Trp128Ter), were reported in a broader genomic evaluation of intellectual disability patients (PMID:27431290). Although segregation details beyond the probands were not extensively detailed, the convergence of independent case reports reinforces the genetic contribution of UBE4A variants to the intellectual disability phenotype.

At the functional level, studies demonstrated that biallelic loss‑of‑function of UBE4A results in reduced RNA expression and protein levels in patient samples. Moreover, murine models engineered to mimic the patient‑specific loss‑of‑function recapitulated key neurological and behavioral abnormalities, which are in concordance with the clinical features observed in affected individuals. These functional data underscore a mechanism likely driven by deficient UBE4A enzyme activity required for normal neurological development and function.

In addition to the genetic and experimental evidence, the shared phenotypic spectrum across different cohorts underscores the clinical relevance of UBE4A testing for patients with intellectual disability. The integration of these data not only supports strong evidence for the gene‑disease relationship but also expands the diagnostic utility of genomic testing for intellectual disability, thereby informing clinical decision‑making and potential therapeutic strategies.

Key Take‑home: The robust association between biallelic UBE4A loss‑of‑function variants and intellectual disability makes genetic testing for UBE4A variants a valuable tool in the diagnostic evaluation of affected individuals.

References

• Genetics in medicine : official journal of the American College of Medical Genetics • 2021 • Biallelic UBE4A loss‑of‑function variants cause intellectual disability and global developmental delay PMID:33420346
• Molecular psychiatry • 2017 • Clinical genomics expands the morbid genome of intellectual disability and offers a high diagnostic yield PMID:27431290

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