Submission Details

UBA5 was first reported with an autosomal recessive developmental and epileptic encephalopathy (DEE) in 2016 (Muona 2016, PMID: 27545674 and Colin 2016, PMID: 27545681). Currently, at least 38 individuals have been reported with UBA5-related DEE. The majority of reported individuals have early-onset encephalopathy with or without seizures, abnormal tone, movement abnormalities, severe global delay, intellectual disability, visual impairment, acquired microcephaly, and significant failure to thrive. However, two siblings with a progressive childhood-onset cerebellar ataxia with normal intellect were also reported to have a missense and nonsense UBA5 variant in trans (Duan 2016, PMID: 26872069). Additionally, five individuals from a large consanguineous family had a severe congenital neuropathy that resulted in death in early infancy due to respiratory failure and carried a homozygous missense variant with significantly decreased activity (Cabrera-Serrano 2020, PMID: 32179706). These cases were not curated for DEE. These two families may suggest a wider phenotypic spectrum of UBA5-related DEE, which may depend on the functional activity and location of the UBA5 variants detected. Therefore, we have split this curation into two disease entities; this curation represents the relationship between UBA5 and autosomal recessive DEE only, with additional studies needed to determine the complete genotype-phenotype spectrum for UBA5-related DEE.

Ten missense, four nonsense, one frameshift, and two whole gene deletions reported in sixteen probands across six publications (PMIDs: 27545674, 27545681, 33811063, 29902590, 30078785, and 40217280) were included in this curation. A recurrent hypomorphic variant (NM_024818.6:c.1111G>A, p.Ala371Thr) has been reported in the compound heterozygous state in several of these individuals (PMIDs: 27545674, 27545681, and 33811063). Additional evidence is available in the literature beyond what is referenced here; however, the maximum score for genetic and experimental evidence has been reached. The mechanism of pathogenicity is loss of function (PMIDs: 27545674, 27545681, and 33811063).

Functional studies of these variants show that affected individuals have a loss-of-function variant in trans with a variant that has some functional activity, suggesting that inheritance of two fully non-functional variants is lethal. This is supported by knockout animal models that do not survive (not scored, PMIDs: 21304510, 27545681, and 26872069).

In summary, there is definitive evidence to support the relationship between UBA5 and autosomal recessive developmental and epileptic encephalopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel on August 5, 2025 (SOP version 11).