Molecular genotype-phenotype correlation in ACTB- and ACTG1-related non-muscle actinopathies

Di Donato, Nataliya, Thom, Andrew, Rump, Andreas, Greve, Johannes N., Cadiñanos, Juan, Calabro, Salvatore, Cathey, Sara, Chung, Brian, Cope, Heidi, Costales, Maria, Cuvertino, Sara, Dinkel, Philine, Erripi, Kalliopi, Fry, Andrew E. ORCID: https://orcid.org/0000-0001-9778-6924, Garavelli, Livia, Hoffjan, Sabine, Janzarik, Wibke G., Kreimer, Insa, Mancini, Grazia, Marin-Reina, Purificacion, Meinhardt, Andrea, Niehaus, Indra, Pilz, Daniela, Ricca, Ivana, Simarro, Fernando Santos, Schrock, Evelin, Marquardt, Anja, Taft, Manuel H., Tezcan, Kamer, Thunström, Sofia, Verhagen, Judith, Verloes, Alain, Wollnik, Bernd, Krawitz, Peter, Hsieh, Tzung-Chien, Seifert, Michael, Heide, Michael, Lawrence, Catherine B., Roberts, Neil A., Manstein, Dietmar J., Woolf, Adrian S. and Banka, Siddharth 2026. Molecular genotype-phenotype correlation in ACTB- and ACTG1-related non-muscle actinopathies. American Journal of Human Genetics 113 (2) , pp. 324-341. 10.1016/j.ajhg.2025.12.007

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Abstract

Recent advances in Mendelian genomics reveal the importance of variant-level characterization of allelic disorders. Non-muscle actin isoforms, encoded by the genes ACTB and ACTG1, are the most abundant intracellular proteins, but historically, they are often regarded as merely being “housekeeping” molecules. Here, we illuminate the extraordinary clinical heterogeneity and complex pathobiology of genetic non-muscle actinopathies. To do this, we combine human genomics studies with molecular biology. Strikingly, variants in ACTB and ACTG1 isoforms generate at least eight distinct clinical disorders. A subset of disease-associated missense variants causes dysregulated actin polymerization-depolymerization and neuronal migration defects. In contrast, nonsense, frameshift, and missense variants enhancing protein degradation cause milder phenotypes or are benign. These results emphasize the essential functional aspects of the non-muscle actin isoforms. Critically, they additionally constitute a template for the personalized genetic variant-level-driven management of the pleiotropic allelic single-gene disorders.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine
Publisher:	Cell Press
ISSN:	0002-9297
Date of First Compliant Deposit:	19 January 2026
Date of Acceptance:	8 December 2025
Last Modified:	03 Mar 2026 15:29
URI:	https://orca.cardiff.ac.uk/id/eprint/184017

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