ClinGen Dosage Sensitivity Curation Page

UBE2A

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
16909393 Nascimento (2006): A report of a family with syndromic X-linked intellectual disability where affected males had a nonsense mutation in the 3' end of UBE2A. The female carriers were phenotypically normal and had skewed X-inactivation. A normal non-carrier sister had random X-inactivation. Functional studies were not provided and it is not known if this mutation leads to a protein-degradation.
23685073 Haddad (2013) reported 5 affected males among 2 families. One family with frameshift mutation leading to deletion and the other with a missense mutation affecting highly conserved amino acid in exon 1. Neither was seen in 389 controls. All males had ID and other developmental features.
24053514 Czeschik 2013 reported 8 affected males among 5 families. Patient 6 was found to have a de novo nonsense mutation in exon 6 and presented with intellectual disabilities, skin changes, facial dysmorphism, urogenital anomalies, seizures, heart defect, and additional clinical features. Patients 1-3 from Family A were found to have an intragenic deletion encompassing exons 1-3 of UBE2A. These patients presented with characteristic facial features, severe intellectual disabilities, skin changes, and additional variable features. The remaining families presented with very similar phenotypes and variable missense mutations or non-focal deletions including UBE2A. Additional carrier females were typically phenotypically normal and found to have skewed X inactivation.

Haploinsufficiency phenotype comments:

de Leeuw 2010 (21108393) reports an additional 3 families, 3 patients with similar deletions encompassing SLC25A43,SLC25A5,CXorf56,UBE2A,NKRF, and two non-coding RNA genes,U1andLOC100303728. Moderate to severe intellectual disability (ID), psychomotor retardation, severely impaired/absent speech, seizures,and urogenital anomalies were present in all three patients. Facial dysmorphisms include ocular hypertelorism, synophrys, and a depressed nasal bridge. Though these deletions were not focal to UBE2A, the clinical and dysmorphic features significantly overlapped those observed in males with missense mutations in the literature. 3 female carriers were tested and all had 90%+ skewing.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.