ACTB – Baraitser-Winter syndrome 1

The cytoplasmic ACTB gene has been robustly associated with the autosomal-dominant Baraitser-Winter syndrome 1 phenotype. To date, seven unrelated de novo missense probands have been reported (3 patients [PMID:23756437], 1 patient [PMID:23649928], 2 patients [PMID:34970864], 1 patient [PMID:35401677]), each presenting with the core features of Baraitser-Winter cerebrofrontofacial syndrome.

Inheritance is strictly autosomal dominant with all variants arising de novo. No multi-generational segregation has been documented, supporting a high rate of de novo occurrence and full penetrance in heterozygotes.

Genetic evidence comprises seven distinct heterozygous missense changes across the ACTB coding sequence, clustering in regions critical for actin polymerization. Variants reported include c.220G>A (p.Gly74Ser), c.349G>A (p.Glu117Lys), c.478A>G (p.Thr160Ala), and c.1043C>T (p.Ser348Leu), among others, each absent from population databases.

Clinically, affected individuals consistently exhibit ocular coloboma (HP:0000589), bilateral ptosis (HP:0000508), intellectual disability (HP:0001249), and neuronal migration defects such as pachygyria or lissencephaly (HP:0002269). Additional findings include craniofacial dysmorphism and variable organ malformations.

Functional studies demonstrate that patient-derived ACTB variants impair actin polymerization and disrupt cell adhesion. The p.Glu117Lys substitution alters filament assembly in patient fibroblasts and S. cerevisiae models ([PMID:23649928]), while the p.Ser348Leu allele shows dominant-negative growth defects and reduced profilin binding in yeast assays ([PMID:34970864]).

These findings support a gain-of-function or dominant-negative mechanism whereby mutant β-actin perturbs cytoskeletal dynamics, leading to the BRWS phenotype. Concordant cellular and in vivo data reinforce causality and align with the de novo genetic pattern.

Key Take-home: De novo heterozygous ACTB missense mutations are a definitive cause of Baraitser-Winter syndrome 1; targeted ACTB sequencing is critical for accurate diagnosis and genetic counseling.

References

• European journal of human genetics • 2014 • Severe forms of Baraitser-Winter syndrome are caused by ACTB mutations rather than ACTG1 mutations. PMID:23756437
• Human mutation • 2013 • Functional analysis of a de novo ACTB mutation in a patient with atypical Baraitser-Winter syndrome. PMID:23649928
• American journal of medical genetics. Part A • 2022 • A de novo ACTB gene pathogenic variant in identical twins with phenotypic variation for hydrops and jejunal atresia. PMID:34970864
• Frontiers in genetics • 2022 • Identification of a De Novo Heterozygous Missense ACTB Variant in Baraitser-Winter Cerebrofrontofacial Syndrome. PMID:35401677

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