De novo variants in ACTB were first reported individuals with autosomal dominant Baraitser-Winter syndrome (BWS) in 2012 (Rivière et al., PMID 22366783). BWS (initially described in 1988 by Baraitser and Winter) is characterized by distinct facial features (the combination of congenital ptosis, high-arched eyebrows, hypertelorism, ocular coloboma) and cerebral malformations ( anterior-predominant lissencephaly, microcephaly) with other abnormalities. Phenotypic variability has been reported. The mechanism of pathogenicity is known to be de novo gain-of-function. Interestingly, loss -of -function variants in this gene have been purported to cause a different neurodevelopmental disorder (described in PMID: 29220674); these variants were not considered as part of this curation. At least eleven missense variants have been reported in 18 probands with BWS across six publications (PMIDs: 23756437, 23649928, 22366783, 29388391, 25052316, 16685646). This gene-disease relationship is also supported by a G-actin polymerization assay with yeast (PMID 23649928), in vitro functional assays, and immunofluorescence staining with patient derived lymphoblastoid cell (PMIDs: 22366783, 16685646). In summary, ACTB is definitively associated with autosomal dominant Baraitser-Winter syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This was approved by the ClinGen Brain Malformations GCEP on October 26, 2021.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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