ACTB deletions or single-nucleotide loss-of-function variants: expansion and further delineation of the phenotype and review of the literature
Year: 2025
Type: article
Study design: Observational Study
Abstract: Background Pathogenic gain-of-function or dominant-negative effect missense variations in ACTB are associated with a neurodevelopmental disorder characterised by intellectual disability (ID), seizures, sensorineural hearing loss, cerebral, renal and ocular abnormalities and dysmorphic features (Baraitser-Winter cerebrofrontofacial syndrome). ACTB encodes beta-actin, a highly conserved protein involved in cell motility, structure and integrity. Deletions including ACTB, and, more rarely, single-nucleotide loss-of-function variants in ACTB have been described in patients with a distinct phenotype including developmental delay, ID, microcephaly, growth restriction, cardiac and renal abnormalities and dysmorphic features. Methods We collected 14 individuals and 1 fetus carrying a heterozygous deletion including ACTB , and 4 individuals with a heterozygous truncating variant. Genotypic and phenotypic data were analysed. Furthermore, a comprehensive review of all cases reported to date was also undertaken. Results Twelve out of 17 individuals presented with ID, and 3 out of 17 with learning disabilities. Speech delay and behavioural abnormalities were observed in 15 out of 17 and 12 out of 17 individuals, respectively, motor delay in 9 out of 17 and growth restriction in 9 out of 18. Most of the individuals (13/18) had recognisable dysmorphic features. 11 anomalies were de novo, except for 1 deletion inherited from the mother. The size of the deletion varied from 125 kb to 1.6 Mb and could result from a fork stalling and template switching. Conclusion This study allowed us to better characterise the phenotype associated with the haploinsufficiency of ACTB, underlying the high prevalence of neurodevelopmental disorders (ID, speech and motor delay, behavioural abnormalities) and growth restriction in this recognisable syndrome.
Source: Journal of Medical Genetics
Authors: Marion Lesieur-Sebellin, Kristen Wigby, Elise Schaefer, Aurélie Gouronc, Nicolas Chatron, Anne-Lise Poulat, Audrey Putoux, Alice Goldenberg, Mathilde Quibeuf, Pascal Chambon, Sophie Rondeau, Giulia Barcia, Jonathan Levy, Juliette Piard, Paul Kuentz, Martine Doco-Fenzy, Nathalie Bednarek, Roseline Caumes, Sonia Bouquillon, Cedric Le Caignec, Olivier Patat, Philippe Khau Van Kien, Jean Chiesa, Geoffroy Delplancq, Séverine Bacrot, Sophie Brisset, Emmanuelle Ginglinger, Vincent Cantagrel, Jerica Lenberg, Jennifer R Friedman, Marlène Rio, Sophie Scheidecker, Valerie Malan
Institutions: Hôpital Necker-Enfants Malades, Inserm, Université Paris Cité, Institut des Maladies Génétiques Imagine, Rady Children's Institute for Genomic Medicine, University of California, Davis, Hôpitaux Universitaires de Strasbourg, Centre National de la Recherche Scientifique, Hospices Civils de Lyon, Institut NeuroMyoGène, Laboratoire Physiopathologie et Génétique du Neurone et du Muscle, Institut NeuroMyoGène - Appui à la recherche, Lyon 1 Université, Centre de Recherche en Neurosciences de Lyon, Centre Hospitalier Universitaire de Rouen, Université de Rouen Normandie, Assistance Publique – Hôpitaux de Paris, Hôpital Robert-Debré, Université de Bourgogne, Centre Hospitalier Universitaire de Besançon, Centre de recherche Translationnelle en Médecine moléculaire, Université de Franche-Comté, Centre Hospitalier Universitaire de Nantes, Centre Hospitalier Universitaire de Reims, Hôpital Jeanne de Flandre, Centre Hospitalier Universitaire de Toulouse, Hôpital Purpan, Toulouse NeuroImaging Center, Centre Hospitalier Universitaire de Nîmes, Centre Hospitalier de Versailles, Hopitaux Civils de Colmar, Rady Children's Hospital-San Diego
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W4414939983