ACTB – Baraitser-Winter cerebrofrontofacial syndrome

Baraitser-Winter cerebrofrontofacial syndrome (BWCFF; MONDO_0017579) is a rare autosomal dominant disorder characterized by distinctive craniofacial features, ocular coloboma, neuronal migration defects, intellectual disability, and multi-organ malformations. Heterozygous missense mutations in the β-actin gene (ACTB; HGNC:132) have been shown to underlie BWCFF, with de novo occurrence in the majority of cases.

Multiple large cohort studies have established a definitive gene–disease relationship. In an exome sequencing study of 18 proband–parent trios and 15 additional patients, de novo ACTB missense variants were identified in all cases, including recurrent p.Arg196His and p.Arg196Cys alleles ([PMID:22366783]). An update of 41 patients reported 34 unrelated individuals harboring ACTB mutations causing BWCFF ([PMID:27240540]). Case reports further expand the phenotypic spectrum to include renal, cardiac, and immunological anomalies ([PMID:24211661]).

All ACTB variants in BWCFF are missense changes affecting highly conserved residues, consistent with a gain-of-function mechanism. The prototypical variant c.586C>T (p.Arg196Cys) has been observed recurrently in unrelated patients ([PMID:22366783]; [PMID:24211661]). No pedigrees with segregation beyond de novo events have been reported for ACTB-associated BWCFF, and affected relatives count is zero.

Functional studies corroborate the pathogenicity of ACTB missense alleles. The p.Ser348Leu variant was modeled in yeast, demonstrating a dominant growth defect and impaired actin function at 22 °C ([PMID:34970864]). A c.478A>G (p.Thr160Ala) mutation expressed in patient peripheral blood mononuclear cells altered actin ATPase activity and filament organization ([PMID:35401677]). These data support a dominant-negative or neomorphic mechanism disrupting actin dynamics.

In summary, over 50 unrelated probands with de novo ACTB missense variants have been reported, with concordant clinical and experimental evidence defining BWCFF. The genetic and functional concordance meets definitive ClinGen criteria for a gene–disease association.

Key Take-Home: ACTB missense mutations are a definitive cause of Baraitser-Winter cerebrofrontofacial syndrome and should be included in diagnostic gene panels for developmental brain and craniofacial malformations.

References

• Nature Genetics • 2012 • De novo mutations in the actin genes ACTB and ACTG1 cause Baraitser-Winter syndrome. [PMID:22366783]
• American Journal of Medical Genetics Part A • 2016 • Update on the ACTG1-associated Baraitser-Winter cerebrofrontofacial syndrome. [PMID:27240540]
• European Journal of Medical Genetics • 2014 • Cerebro-fronto-facial syndrome type 3 with polymicrogyria: a clinical presentation of Baraitser-Winter syndrome. [PMID:24211661]
• 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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