Submission Details

The UBA2 gene, located on chromosome 19 at 19q13.11, encodes a ubiquitin-like modifier activating enzyme that forms a heterodimer with SAE1 and binds to SUMO proteins, initiating SUMOylation (post-translational protein-modification similar to ubiquitination). UBA2 was first reported in relation to autosomal dominant ACCES syndrome in 2017 (Marble et al. PMID: 28110515). ACCES syndrome is characterized by aplasia cutis congenita (ACC), limb anomalies, early growth deficiency, developmental delay, with clinical heterogeneity. Additionally, UBA2 has been identified as a driver of the ACC phenotype in 19q13.11 microdeletion syndrome (Abe et al. 2018, PMID: 29988626). Eight unique variants, including seven truncating and one missense, that have been reported in 8 families across six publications (PMID: 28110515; Yamamoto et al. 2019, PMID: 31332306; Wang et al. 2020, PMID: 31587267; Aerden et al. 2020, PMID: 32758660; Schnur et al. 2021, PMID: 34040189; Elsner et al. 2021, PMID: 34159400) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by a zebrafish model (PMID: 34040189). In summary, there is definitive evidence supporting the relationship between UBA2 and autosomal dominant ACCES syndrome. 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 Syndromic Disorders GCEP on the meeting date September 4, 2024 (SOP Version 10).