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:
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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/

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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
- metadata checks passed: 4
- metadata issues found: 0

Metadata Audited:
- article_doi
- article_title
- article_journal
- license

Factual Items Audited:
- Cohort comprises 290 individuals with ACTB/ACTG1 variants (125 new cases)
- Eight distinct non-muscle actinopathies (NMAs) identified
- BWCFF associated with missense variants showing decreased actin polymerization and faster depolymerization
- ACTB loss-of-function (LoF) variants/deletions associated with thrombocytopenia and mild neurodevelopmental impairment
- ACTG1 deletions often milder or near-normal; dosage sensitivity lower than ACTB
- Dystonia-deafness syndrome (ACTB hotspot variants like R183W) and isolated hearing loss (ACTG1) described

QC result: Pass.