281: Variant-level mapping of ACTB and ACTG1 defines eight non-muscle actinopathies and links BWCFF to actin polymerization defects

Di Donato N et al., The American Journal of Human Genetics, 113 (2026) 324-341. doi:10.1016/j.ajhg.2025.12.007 - 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. Key terms: ACTB, ACTG1, Baraitser-Winter, actin polymerization, genotype-phenotype. 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. Music:Enjoy the music based on this article at the end of the episode. Article title:Molecular genotype-phenotype correlation in ACTB- and ACTG1-related non-muscle actinopathies First author:Di Donato N Journal:The American Journal of Human Genetics, 113 (2026) 324-341. doi:10.1016/j.ajhg.2025.12.007 DOI:10.1016/j.ajhg.2025.12.007 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/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/actb-actg1-non-muscle-actinopathies QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2026-02-06. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the substantive scientific content of the transcript, focusing on: gene pair ACTB/ACTG1; eight NMAs; BWCFF mechanistic basis (actin polymerization/depolymerization); loss-of-function ACTB with thrombocytopenia; ACTG1 deletion phenotypes; fibroblast/tissue specificity; GestaltMatcher-based facial analysis; diagn- transcript topics: ACTB and ACTG1 gene similarity and functional differences; Cohort overview: 290 individuals, 125 new cases; Eight non-muscle actinopathies (NMAs) and genotype-phenotype correlations; BWCFF mechanism: missense variants cause unstable actin, altered polymerization/depolymerization; ACTB loss-of-function (LoF) disorder: thrombocytopenia and neurodevelopmental features; ACTG1 deletions: milder phenotypes or near-normal presentations QC Summary:- factual score: 10/10- metadata score: 10/10- supported core claims: 7- claims flagged for review: 0