ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000007.13) (NC_000007.14)
  • Haploinsufficiency score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Haploinsufficiency phenotype comments:

Heterozygous missense mutations within the ACTB gene have been described in patients with Baraitser-Winter syndrome 1. The missense mutations are thought to be gain of function or dominant-negative mutations. Riviere et al. (2012) (PMID:22366783) put forth the following pieces of evidence arguing against haploinsufficiency of ACTB as a mechanism for this condition: "Firstly, none of our subjects had deletions or protein-truncating mutations...Further, 11 of 18 mutations (61%) disrupt the same two amino-acids (ACTB Arg196 and ACTG1 Ser155)... Second, patients with complete deletion or duplication of ACTB do not have Baraitser-Winter syndrome. To assess the latter, we searched the databases of two large clinical laboratories performing chromosome microarrays, Signature Genomic Laboratories and the Department of Human Genetics, Radboud University Nijmegen Medical Centre, and ascertained four children: two with a deletion and one with a duplication of 7p22 that included ACTB, and one with a deletion of 17q25.3 that included ACTG1. All lacked the major and most severe features of Baraitser-Winter syndrome, which are congenital ptosis and high-arched eyebrows, neuronal migration malformation and colobomata... Finally, the unchanged ?- and ?-actin protein levels coupled with increased F-actin content observed in patient-derived lymphoblastoid cell lines also argue against haploinsufficiency." There has been a single case report describing monozygotic twins with a missense mutation in ACTB and a different phenotype that includes developmental midline malformations, sensory hearing loss and delayed onset generalized dystonia (described in OMIM as "juvenile-onset dystonia." No ACTB mutation was identified in the mother or two half brothers. Father was unavailable for testing. Not seen in 117 unrelated controls (16685646).

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

Triplosensitivity phenotype comment:

Of note, Preiksaitiene et al. (2012) (PMID: 22495914) report an individual with a 1Mb duplication of 7p22.1 and mild intellectual disability, macrocephaly, ocular hypertelorism, low-set ears, and other features. The authors note that this duplication contains ACTB as well as 14 other RefSeq genes. It is unclear whether duplication of any of these other genes is contributing to this phenotype.