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Aplasia Cutis Congenita with Ectrodactyly Skeletal Syndrome (UBA2 – ACCES syndrome) is a rare autosomal dominant multiple congenital anomaly disorder characterized by growth retardation, dysmorphic facial features, neurodevelopmental delay, skeletal malformations including ectrodactyly, developmental dysplasia of the hip and scoliosis, and skin aplasia. Haploinsufficiency of UBA2 underlies the phenotype.
A novel heterozygous splice-site variant, c.460-2A>G, was identified by exome sequencing in a 13-year-old female proband with disproportionate short stature (HP:0003498), scoliosis (HP:0002650), and lumbar hyperlordosis (HP:0002938) and her affected father, demonstrating co-segregation and autosomal dominant inheritance (PMID:39149811).
In a multicenter series, 16 additional probands from seven unrelated families harbored heterozygous loss-of-function and missense variants in UBA2, including nonsense variant c.364C>T (p.Arg122Ter) and frameshift variants, each segregating with ACCES syndrome features across pedigrees (PMID:34040189).
Co-segregation analysis across these families demonstrated at least one additional affected relative per pedigree, reinforcing dominant inheritance and variant pathogenicity.
Functional modeling in zebrafish showed that uba2-null embryos recapitulate growth deficiency, microcephaly, microphthalmia, mandibular hypoplasia, and fin defects, and that wild-type human UBA2 mRNA rescues the phenotype while mRNAs carrying human missense variants fail to restore normal development, confirming a loss-of-function mechanism (PMID:34040189).
Collectively, heterozygous UBA2 variants cause ACCES syndrome via haploinsufficiency of the SUMO-activating enzyme, supporting UBA2 molecular testing in patients with aplasia cutis congenita and skeletal dysplasia.
Key Take-home: UBA2 haploinsufficiency reliably underlies ACCES syndrome and should be considered in dominant congenital skeletal malformation disorders.
Gene–Disease AssociationStrong18 probands in 8 families with familial segregation and concordant functional data Genetic EvidenceStrong16 probands across 7 unrelated families and a father–daughter pair; LoF and missense variants segregate with disease; genetic evidence cap reached Functional EvidenceModerateZebrafish uba2-null model recapitulates ACCES features and human variant mRNAs fail to rescue phenotype |