PURPOSE: This study aims to comprehensively delineate the phenotypic spectrum of ACTL6B-related disorders, previously associated with both autosomal recessive and autosomal dominant neurodevelopmental disorders. Molecularly, the role of the nucleolar protein ACTL6B in contributing to the disease has remained unclear. METHODS: We identified 105 affected individuals, including 39 previously reported cases, and systematically analyzed detailed clinical and genetic data for all individuals. Additionally, we conducted knockdown experiments in neuronal cells to investigate the role of ACTL6B in ribosome biogenesis. RESULTS: Biallelic variants in ACTL6B are associated with severe-to-profound global developmental delay/intellectual disability, infantile intractable seizures, absent speech, autistic features, dystonia, and increased lethality. De novo monoallelic variants result in moderate-to-severe global developmental delay/intellectual disability, absent speech, and autistic features, whereas seizures and dystonia were less frequently observed. Dysmorphic facial features and brain abnormalities, including hypoplastic corpus callosum, and parenchymal volume loss/atrophy, are common findings in both groups. We reveal that in the nucleolus, ACTL6B plays a crucial role in ribosome biogenesis, particularly in pre-rRNA processing. CONCLUSION: This study provides a comprehensive characterization of the clinical spectrum of both autosomal recessive and dominant forms of ACTL6B-associated disorders. It offers a comparative analysis of their respective phenotypes provides a plausible molecular explanation and suggests their inclusion within the expanding category of "ribosomopathies."

Aix Marseille Univ APHM department of Pediatrics Neurology Timone children Hospital Marseille France

Aix Marseille Univ Inserm MMG Marseille France Service de Génétique Médicale AP HM Hôpital de La Timone Marseille France

Al Quds University Jerusalem Palestine

Cellular Molecular and Genetics Research Center Isfahan University of Medical Sciences Isfahan Iran; Medical Genetics Research Center of Genome Isfahan University of Medical Sciences Isfahan Iran

CENTOGENE GmbH Rostock German

Centre Mohamed 6 for Research and Innovation Benguerir Morocco

CHU Sainte Justine Research Center Montreal QC Canada; Department of Pediatrics Faculty of Medicine Université de Montréal Montreal QC Canada

Clinical Genetic Services Department of Pediatrics NYU Grossman School of Medicine New York NY; Clinical Genetics NYU Orthopedic Hospital New York NY

Clinical Genetics Center for Children Hassenfeld Children's Hospital New York University New York NY

Clinical Genetics Department Human Genetics and Genome Research Institute National Research Centre Cairo Egypt

Clinical Genetics service Northampton General Hospital Northampton United Kingdom

Clinical Research Centre Sunway Medical Centre Malaysia

College of Medicine University of Baghdad Unit of Pediatric Neurology Children Welfare Teaching Hospital Baghdad Iraq

Département de Génétique Médicale Maladies rares et Médecine Personnalisée et Centre de Référence Anomalies du Développement et Syndromes Malformatifs CHRU de Montpellier Montpellier France

Department of Biology and Medical Genetics 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

Department of Cell and Molecular Biology and Microbiology Faculty of Biological Science and Technology University of Isfahan Isfahan Iran

Department of Clinical and Movement Neurosciences UCL Queen Square Institute of Neurology University College London London United Kingdom

Department of Clinical Genetics Erasmus MC Rotterdam The Netherlands

Department of Genetics Hadassah Medical Center Jerusalem Israel Faculty of Medicine Hebrew University of Jerusalem Jerusalem Israe

Department of Genetics Southern California Permanente Medical Group Fontana CA

Department of Human Genetics Radboudumc University Medical Center Nijmegen The Netherlands; Donders Institute for Brain Cognition and Behaviour Radboud University Nijmegen The Netherlands

Department of Human Genetics The University of Chicago Illinois

Department of Medical Genetics and Molecular Medicine School of Medicine Medical Genetics Research Center Mashhad University of Medical Sciences Mashhad Iran

Department of Medical Genetics Faculty of Medicine Shahid Beheshti University of Medical Sciences Tehran Iran

Department of Medical Genetics Next Generation Genetic Polyclinic Mashhad Iran; Molecular and Clinical Sciences Institute St George's University of London Cranmer Terrace London United Kingdom; Innovative Medical Research Center Mashhad Branch Islamic Azad University Mashhad Iran

Department of Medical Genetics Samsun University Faculty of Medicine Samsun Turkey

Department of Molecular and Human Genetics Baylor College of Medicine Houston TX

Department of Molecular and Human Genetics Baylor College of Medicine Houston TX; Department of Pediatrics Faculty of Medicine Kuwait University Safat Kuwait

Department of Molecular and Human Genetics Baylor College of Medicine Houston TX; Human Genome Sequencing Center Baylor College of Medicine Houston TX; Department of Pediatrics Baylor College of Medicine Houston TX

Department of Molecular and Human Genetics Baylor College of Medicine Houston TX; Section of Pediatric Neurology and Developmental Neuroscience Department of Pediatrics Baylor College of Medicine Houston TX

Department of Neuromuscular Diseases University College London Queen Square Institute of Neurology London United Kingdom

Department of Neuromuscular Diseases University College London Queen Square Institute of Neurology London United Kingdom; Human Genetics Department Medical Research Institute Alexandria University Egypt

Department of Neuromuscular Diseases University College London Queen Square Institute of Neurology London United Kingdom; Palindrome Isfahan Iran

Department of Neuropediatric University Hospital of Lyon Lyon France

Department of Neurosciences Rehabilitation Ophthalmology Genetics Maternal and Child Health University of Genoa Genoa Italy

Department of Neurosciences Rehabilitation Ophthalmology Genetics Maternal and Child Health University of Genoa Genoa Italy; Pediatric Neurology and Muscular Diseases Unit IRCCS Istituto Giannina Gaslini Genova Italy

Department of Neurosciences Unit of Neurorehabilitation Bambino Gesù Children's Hospital IRCCS Rome Italy

Department of Neurosciences University of California San Diego La Jolla CA; Rady Children's Institute for Genomic Medicine San Diego CA

Department of Paediatric and Child Health Aga Khan University Hospital Karachi Pakistan

Department of Paediatric Neurology Children Hospital and Institute of Child Health Faisalabad Pakistan

Department of Paediatric Neurology Children's Hospital and Institute of Child Health Multan Pakistan

Department of Paediatrics and Genetics Universidade Federal de Paraiba Joao Pessoa Paraiba Brazil

Department of Paediatrics Murdoch Children's Research Institute and University of Melbourne Royal Children's Hospital Melbourne Australia

Department of Pediatric Gastroenterology Hepatology and Genetic diseases Children's Hospital and University of Child Health Sciences Lahore Pakistan

Department of Pediatric Neurology Indira Gandhi Institute of Child Health Bengaluru India

Department of Pediatric Neurology Instituto de Medicina Integral Prof Fernando Figueira Boa Vista Recife Brazil

Department of Pediatric Neurology Neo Clinic Children's Hospital Jaipur India

Department of Pediatrics Boston Children's Hospital Harvard Medical School Boston MA

Department of Pediatrics Faculty of Medicine Sohag University Sohag Egypt

Department of Pediatrics Fayoum University Hospitals Fayoum Egypt

Department of Pediatrics Vanderbilt Kennedy Center Vanderbilt University Medical Center Nashville TN

Department of Physiology Perelman School of Medicine University of Pennsylvania Philadelphia PA

Department of Radiology Neuroradiology Section Kingston Health Sciences Centre Queen's University Faculty of Health Sciences Kingston Ontario Canada

Department of Translational Genomics Center for Genomic Medicine King Faisal Specialist Hospital and Research Center Riyadh Saudi Arabia

Division of Genetics Arnold Palmer Hospital for Children Orlando Health Orlando FL

Division of Medical Genetics 3billion Inc Seoul South Korea

Faculty of Medical Sciences Mohammed 6 Polytechnic University of Benguerir Ben Guerir Morocco

GeneDx Gaithersburg MD

Genetic Center Akron Children's Hospital Akron OH

Genetics of Non Communicable Disease Research Center Zahedan University of Medical Sciences Zahedan Iran

Genomic Medicine Center Children's Mercy Hospital Kansas City MO; Kansas City School of Medicine University of Missouri Kansas City MO; Department of Pathology and Laboratory Medicine Children's Mercy Hospital Kansas City MO

Genomic Research Center Shahid Beheshti University of Medical Sciences Tehran Iran

Great Ormond Street Hospital for Children NHS Foundation Trust London United Kingdom

Hospices Civils de Lyon Service de Génétique Bron France; Pathophysiology and Genetics of Neuron and Muscle Université Claude Bernard Lyon 1 Lyon France

Institute of Human Genetics University of Leipzig Medical Center Leipzig Germany

Instituto de Medicina Integral Prof Fernando Figueira Centro de Terapias Cetogênicas do IMIP Recife PE Brazil

İzmir Katip Çelebi University Tepecik Training and Research Department of Pediatric Neurology Izmir Turkey

Laboratório Mendelics Department of Genetic São Paulo Brazil

Laboratory of Medical Genetics Medical School National and Kapodistrian University of Athens St Sophia's Children's Hospital Athens Greece

Laboratory of Medical Genetics Translational Cytogenomics Research Unit Bambino Gesù Children Hospital IRCCS Rome Italy

Maternal Fetal and Neonatal Research Center Family Health Research Institute Tehran University of Medical Sciences Tehran Iran; Genetics Ward Yas Hospital Complex Tehran University of Medical Sciences Tehran Iran

Medical Molecular Genetics Department Human Genetics and Genome Research Institute National Research Centre Cairo Egypt

Mendelics Genomic Analysis São Paulo Brazil

Molecular Genetics Laboratory Istishari Arab Hospital Ramallah Palestine

Neurology Unit Department of Pediatrics Faculty of Medicine Alexandria University Egypt

NIHR Biomedical Research Centre Centre for Human Genetics University of Oxford Oxford United Kingdom

Oxford Genetics Laboratories Oxford University Hospitals NHS Foundation Trust Oxford United Kingdom

Paediatrics Wah Medical College NUMS Wah Cantonment Punjab Pakistan

Palindrome Isfahan Iran

Pardis Pathobiology and Genetics Laboratory Mashhad Iran

PRCS hospital Hebron Palestine

Research Centre for Medical Genetics Moscow Russia

RNA Molecular Biology Fonds de la Recherche Scientifique Biopark campus Gosselies Belgium

Section of Pediatric Neurology and Developmental Neuroscience Department of Pediatrics Baylor College of Medicine Houston TX

Service de Génétique Clinique CHU Lille Lille France

Service de génétique médicale CHU de Nantes Nantes France; Institut du thorax INSERM CNRS UNIV Nantes Nantes France

Sulaiman Al Habib Hospital Olaya Medical Complex Riyadh Saudi Arabia

The Community Health Clinic Shipshewana IN

UK National Paediatric Ataxia Telangiectasia Clinic Nottingham University Hospitals NHS Trust Nottingham United Kingdom; Nottingham Clinical Genetics Service Nottingham University Hospitals NHS Trust Nottingham United Kingdom

Unité Fonctionnelle 6254 d'Innovation en Diagnostique Génomique des Maladies Rares Pôle de Biologie CHU Dijon Bourgogne Dijon France; INSERM UMR1231 GAD Dijon France

Unité Fontctionnelle d'Innovation diagnostiques des maladies rares FHU TRANSLAD CHU Dijon Bourgogne Dijon France; INSERM Université de Bourgogne UMR1231 GAD Génétique des Anomalies du Développement Dijon France

University of Chicago Medicine University of Chicago Chicago IL

University of Health Sciences Gülhane Faculty of Medicine Department of Child Neurology Ankara Turkey

Veltischev Research and Clinical Institute for Pediatrics of the Pirogov Russian National Research Medical University Ministry of Health of Russian Federation Moscow Russia; Mental Health Research Center Moscow Russia

West Midlands Clinical Genetics Service Birmingham Women's Hospital Birmingham United Kingdom

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