Di Donato N et al., The American Journal of Human Genetics. 113:324-341 ( - Analysis of 290 individuals with ACTB and ACTG1 variants defines eight distinct non-muscle actinopathies and links BWCFF-causing variants to altered actin polymerization dynamics.

Study Highlights:
The study assembled a clinical-genomic cohort of 290 individuals with P/LP ACTB or ACTG1 variants and used expert phenotyping plus GestaltMatcher facial analysis to delineate eight distinct non-muscle actinopathies. Complementary methods included patient-derived fibroblast transcriptomics, recombinant actin production, differential scanning fluorimetry, and pyrene-based polymerization/depolymerization assays. BWCFF-associated missense variants (e.g., ACTB:R196H, ACTG1:T203M) produced decreased polymerization rates and faster depolymerization, whereas selected ACTB missense or in-frame variants impaired folding or thermal stability consistent with loss-of-function. These mechanistic stratifications support improved diagnostic classification, prognostication, and selection of functional assays for variant interpretation.

Conclusion:
Variant-level analysis of 290 individuals delineates eight distinct non-muscle actinopathies and shows that BWCFF-linked missense variants disrupt actin polymerization while select ACTB variants cause protein instability consistent with loss-of-function.

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Reference:
Di Donato N, NMA Consortium, et al. Molecular genotype-phenotype correlation in ACTB- and ACTG1-related non-muscle actinopathies. The American Journal of Human Genetics. 113:324-341 (2026). https://doi.org/10.1016/j.ajhg.2025.12.007

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) - https://creativecommons.org/licenses/by/4.0/

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