Submission Details

The UBE2A gene has been associated with syndromic X-linked intellectual disability (ID) using the ClinGen Validity Framework as of June 19, 2018. This association was made using Case-level data only. At At least 10 unique variants, including missense, nonsense, frameshift, splice-site and large intragenic deletion, have been reported in humans. UBE2A was first associated with this disease ( and a synonymous disease nomenclature of UBE2A deficiency syndrome) in humans as early as 2006 (Nascimento et al., 2006 PMID: 16909393). The syndrome is associated with familial and de novo transmission in humans, and has been observed in at least 10 probands in 7 publications. Furthermore, CNV at this locus on the X-chromosome (Xq24) is also associated with ID with overlapping phenotypes, indicating UBE2A as a causative gene for ID. The mechanism for disease is loss of function (LOF). The gene-disease association is supported by biochemical studies (as it is a ubiquitin proteasome pathway) and animal models. In summary, UBE2A is definitively associated with syndromic X-linked ID. 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 Autism and Intellectual Disability Expert Panel on July 2, 2018.

UBE2A was first reported in relation to syndromic X-linked intellectual disability Nascimento type, also known as UBE2A deficiency syndrome, in 2006 (Nascimento et al., PMID: 16909393). In addition to sequence variants, deletion copy number variants at the Xq24 locus are associated with intellectual disability with overlapping phenotypes, indicating UBE2A is a causative gene for intellectual disability.

Ten variants (missense, nonsense, frameshift, splice-site and large intragenic deletion) that have been reported in 10 probands in 6 publications (PMIDs: 16909393, 20412111, 23685073, 24053514, 28611923, 29283210) are included in this curation. The syndrome is associated with familial and de novo inheritance. The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by biochemical studies (ubiquitin proteasome pathway) and animal models.

In summary, there is definitive evidence supporting the relationship between UBE2A and syndromic X-linked intellectual disability Nascimento type. 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 Intellectual Disability and Autism Gene Curation Expert Panel on July 2, 2018 (SOP Version 5).