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Baraitser-Winter cerebrofrontofacial syndrome (BWCFF) is a rare autosomal dominant developmental disorder characterized by distinctive craniofacial dysmorphism, neuronal migration defects and ocular colobomata. Heterozygous missense mutations in the gamma-actin gene ACTG1 underlie BWCFF, disrupting cytoskeletal dynamics critical for facial and brain morphogenesis. The association between ACTG1 and BWCFF was first established through trio whole-exome sequencing and cohort screening, revealing recurrent de novo missense variants in ACTG1 in affected individuals. These findings are supported by multiple independent case reports and family studies that document both sporadic and inherited presentations of BWCFF due to ACTG1 alterations. ACTG1 is ubiquitously expressed, and its pathogenic variants lead to dominant-negative effects on actin polymerization in neuronal and craniofacial tissues. Genetic testing for ACTG1 accurately diagnoses BWCFF and guides clinical management.
The inheritance mode of ACTG1-related BWCFF is autosomal dominant. In a cohort of 18 unrelated probands, de novo ACTG1 missense changes were identified, with c.464C>T (p.Ser155Phe) observed recurrently (PMID:22366783). Segregation analysis in a three-generation pedigree with a novel ACTG1 mutation confirmed transmission in two additional affected relatives (PMID:27096712). A report of adult siblings revealed germline mosaicism leading to two cases in one family, further supporting dominant inheritance (PMID:32506774). Collectively, 21 probands with ACTG1 variants have been documented in both sporadic and familial contexts. The weight of this genetic evidence supports a Definitive gene–disease association.
All pathogenic ACTG1 variants in BWCFF are missense, clustering in highly conserved actin domains. Recurrent de novo changes include c.464C>T (p.Ser155Phe) in seven unrelated individuals and c.377C>T (p.Thr126Ile) in two (PMID:22366783). Segregation of ACTG1 mutations has been demonstrated in three-generation pedigrees and sibling pairs, accounting for at least three additional affected relatives beyond probands (PMID:27096712; PMID:32506774). No loss-of-function or large structural variants have been reported, highlighting a specific missense mechanism. Phenotypic variability ranges from classic BWCFF facial gestalt to partial presentations with isolated hearing loss or growth hormone deficiency. Carrier frequency is exceedingly low given the rarity of the syndrome.
Functional studies demonstrate that BWCFF-associated ACTG1 variants impair filament stability and interactions with regulatory proteins. In yeast models, mutant F-actin filaments are hypersensitive to cofilin-mediated disassembly, indicating a dominant-negative mechanism (PMID:19419963). Cellular assays show aberrant actin bundling and impaired polymerization kinetics, consistent with disrupted cytoskeletal networks. Structural analyses of gamma-actin filaments reveal conformational shifts at the mutation sites affecting interprotomer contacts. These findings align with the neurodevelopmental phenotypes observed in patients and support a Moderate level of functional evidence.
No studies have refuted the role of ACTG1 in BWCFF. Mutations in the related ACTB gene can cause more severe Baraitser-Winter phenotypes, but ACTG1 variants define a distinct, generally milder spectrum. Functional assays of ACTB versus ACTG1 mutants reveal isoform-specific effects, with ACTG1 changes predominantly affecting neuronal migration pathways. There is no evidence that ACTG1 variants alone lead to alternative clinical entities unrelated to BWCFF in the reported cohorts.
Overall, ACTG1 demonstrates a Definitive gene–disease relationship with Baraitser-Winter cerebrofrontofacial syndrome, driven by de novo and familial missense mutations in multiple unrelated families. Genetic and experimental data converge on a dominant-negative mechanism disrupting actin dynamics in development. Comprehensive ACTG1 sequencing should be included in diagnostic panels for lissencephaly and craniofacial malformations. Early molecular diagnosis enables anticipatory management of vision, hearing and endocrine complications. Key Take-home: ACTG1 missense mutations are a definitive cause of autosomal dominant Baraitser-Winter cerebrofrontofacial syndrome, with direct implications for diagnosis and genetic counseling.
Gene–Disease AssociationDefinitive18 probands in unrelated families with de novo ACTG1 variants ([PMID:22366783]), segregation in a three-generation pedigree ([PMID:27096712]) Genetic EvidenceStrong18 de novo missense variants in unrelated probands ([PMID:22366783]) and three additional familial segregations ([PMID:27096712]) Functional EvidenceModerateIn vitro and yeast assays show mutant ACTG1 filaments are hypersensitive to cofilin and demonstrate impaired polymerization ([PMID:19419963]) |