Clinical and genetic delineation of autosomal recessive and dominant ACTL6B-related developmental brain disorders

Cali E 1 , Quirin T 2 , Rocca C 1 , Efthymiou S 1 , Riva A 3 , Marafi D 4 Show all authors , Zaki MS 5 , Suri M 6 , Dominguez R 7 , Elbendary HM 5 , Alavi S 8 , Abdel-Hamid MS 9 , Morsy H 10 , Mau-Them FT 11 , Nizon M 12 , Tesner P 13 , Ryba L 13 , Zafar F 14 , Rana N 14 , Saadi NW 15 , Firoozfar Z 16 , Gencpinar P 17 , Unay B 18 , Ustun C 18 , Bruel AL 19 , Coubes C 20 , Stefanich J 21 , Sezer O 22 , Agolini E 23 , Novelli A 23 , Vasco G 24 , Lettori D 24 , Milh M 25 , Villard L 26 , Zeidler S 27 , Opperman H 28 , Strehlow V 28 , Issa MY 5 , El Khassab H 29 , Chand P 30 , Ibrahim S 30 , Nejad-Rashidi A 31 , Miryounesi M 32 , Larki P 32 , Morrison J 33 , Cristian I 33 , Thiffault I 34 , Bertsch NL 35 , Noh GJ 36 , Pappas J 37 , Moran E 38 , Marinakis NM 39 , Traeger-Synodinos J 39 , Hosseini S 40 , Abbaszadegan MR 41 , Caumes R 42 , Vissers LELM 43 , Neshatdoust M 44 , Montazer MZ 45 , El Fahime E 46 , Canavati C 47 , Kamal L 47 , Kanaan M 47 , Askander O 48 , Voinova V 49 , Levchenko O 50 , Haider S 51 , Halbach SS 52 , Maia ER 53 , Mansoor S 54 , Vivek J 55 , Tawde S 56 , Santhosh R Challa V 57 , Gowda VK 57 , Srinivasan VM 57 , Victor LA 58 , Pinero-Banos B 59 , Hague J 60 , Ei-Awady HA 61 , Maria de Miranda Henriques-Souza A 62 , Cheema HA 63 , Anjum MN 63 , Idkaidak S 64 , Alqarajeh F 65 , Atawneh O 65 , Mor-Shaked H 66 , Harel T 66 , Zifarelli G 67 , Bauer P 67 , Kok F 68 , Kitajima JP 68 , Monteiro F 68 , Josahkian J 68 , Lesca G 69 , Chatron N 69 , Ville D 70 , Murphy D 1 , Neul JL 71 , Mullegama SV 72 , Begtrup A 72 , Herman I 73 , Mitani T 74 , Posey JE 74 , Tay CG 75 , Javed I 76 , Carr L 77 , Kanani F 78 , Beecroft F 79 , Hane L 80 , Abdelkreem E 81 , Macek M 13 , Bispo L 82 , Elmaksoud MA 83 , Hashemi-Gorji F 84 , Pehlivan D 85 , Amor DJ 86 , Jamra RA 28 , Chung WK 87 , Ghayoor EK 88 , Campeau P 89 , Alkuraya FS 90 , Pagnamenta AT 91 , Gleeson J 92 , Lupski JR 93 , Striano P 94 , Moreno-De-Luca A 95 , Lafontaine DLJ 2 , Houlden H 1 , Maroofian R 96

Affiliations 

  • 1 Department of Neuromuscular Diseases, University College London, Queen Square, Institute of Neurology, WC1N 3BG London, UK
  • 2 RNA Molecular Biology, Fonds de la Recherche Scientifique (F.R.S./FNRS), Université libre de Bruxelles (ULB), Biopark campus, B-6041 Gosselies, Belgium
  • 3 Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy
  • 4 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA; Department of Pediatrics, Faculty of Medicine, Kuwait University, Safat, Kuwait
  • 5 Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt
  • 6 UK National Paediatric Ataxia Telangiectasia Clinic, Nottingham University Hospitals NHS Trust, Nottingham, UK; Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust, Nottingham, UK
  • 7 Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
  • 8 Department of Neuromuscular Diseases, University College London, Queen Square, Institute of Neurology, WC1N 3BG London, UK; Palindrome, Isfahan, Iran
  • 9 Medical Molecular Genetics Department, Human Genetics and Genome Research Institute, National Research Centre Cairo, Egypt
  • 10 Department of Neuromuscular Diseases, University College London, Queen Square, Institute of Neurology, WC1N 3BG London, UK; Human Genetics Department, Medical Research Institute, Alexandria University, Egypt
  • 11 Unité Fonctionnelle 6254 d'Innovation en Diagnostique Génomique des Maladies Rares, Pôle de Biologie, CHU Dijon Bourgogne, Dijon 21070, France; INSERM UMR1231 GAD, Dijon 21000, France
  • 12 Service de génétique médicale, CHU de Nantes, Nantes, France; Institut du thorax, INSERM, CNRS, UNIV Nantes, Nantes, France
  • 13 Department of Biology and Medical Genetics, 2nd Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic
  • 14 Department of Paediatric Neurology, Children's Hospital and Institute of Child Health, Multan, Pakistan
  • 15 College of Medicine/University of Baghdad, Unit of Pediatric Neurology, Children Welfare Teaching Hospital, Baghdad, Iraq
  • 16 Palindrome, Isfahan, Iran
  • 17 İzmir Katip Çelebi University Tepecik Training and Research Department of Pediatric Neurology, Izmir, Turkey
  • 18 University of Health Sciences, Gülhane Faculty of Medicine, Department of Child Neurology, Ankara, Turkey
  • 19 Unité Fontctionnelle d'Innovation diagnostiques des maladies rares, FHU TRANSLAD, CHU Dijon Bourgogne, Dijon, 21000, France; INSERM-Université de Bourgogne UMR1231 GAD "Génétique des Anomalies du Développement", Dijon, 21078, France
  • 20 Département de Génétique Médicale, Maladies rares et Médecine Personnalisée, et Centre de Référence Anomalies du Développement et Syndromes Malformatifs, CHRU de Montpellier, Montpellier, France
  • 21 Genetic Center, Akron Children's Hospital, Akron, Ohio, USA
  • 22 Department of Medical Genetics, Samsun University, Faculty of Medicine, Samsun, Turkey
  • 23 Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children Hospital, IRCCS, Rome, Italy
  • 24 Department of Neurosciences, Unit of Neurorehabilitation, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
  • 25 Aix-Marseille Univ, APHM, department of Pediatrics Neurology. Timone children Hospital. Marseille, France
  • 26 Aix Marseille Univ, Inserm, MMG, Marseille, France; Service de Génétique Médicale, AP-HM, Hôpital de La Timone, Marseille, France
  • 27 Department of Clinical Genetics, Erasmus MC, 3015 GD Rotterdam, The Netherlands
  • 28 Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
  • 29 Sulaiman Al Habib Hospital - Olaya Medical Complex - Riyadh, Saudi Arabia
  • 30 Department of Paediatric and Child Health, Aga Khan University Hospital, Karachi, Pakistan
  • 31 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
  • 32 Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  • 33 Division of Genetics, Arnold Palmer Hospital for Children, Orlando Health, Orlando, FL 32806, USA
  • 34 Genomic Medicine Center, Children's Mercy Hospital, Kansas City, MO, United States; Kansas City School of Medicine, University of Missouri, Kansas City, MO, United States; Department of Pathology and Laboratory Medicine, Children's Mercy Hospital, Kansas City, MO, United States
  • 35 The Community Health Clinic, Shipshewana, Indiana, USA
  • 36 Department of Genetics, Southern California Permanente Medical Group, Fontana, CA 92335, USA
  • 37 Clinical Genetic Services, Department of Pediatrics, NYU Grossman School of Medicine, New York, NY 10016, USA; Clinical Genetics, NYU Orthopedic Hospital, New York, NY 10010, USA
  • 38 Clinical Genetics, Center for Children, Hassenfeld Children's Hospital, New York University, New York, New York, USA
  • 39 Laboratory of Medical Genetics, Medical School, National and Kapodistrian University of Athens, St. Sophia's Children's Hospital, Athens, Greece
  • 40 Pardis Pathobiology and Genetics Laboratory, Mashhad, Iran
  • 41 Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran; Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
  • 42 Service de Génétique Clinique, CHU Lille, Lille, France
  • 43 Department of Human Genetics, Radboudumc University Medical Center, Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, the Netherlands
  • 44 Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
  • 45 Genetics of Non-Communicable Disease Research Center, Zahedan University of Medical Sciences, Zahedan, Iran
  • 46 National Centre for Scientific and Technical Research, Rabat, Morocco
  • 47 Molecular Genetics Laboratory, Istishari Arab Hospital, Ramallah, Palestine
  • 48 Faculty of Medical Sciences, Mohammed 6 Polytechnic University of Benguerir, Ben Guerir, Morocco
  • 49 Veltischev Research and Clinical Institute for Pediatrics of the Pirogov, Russian National Research Medical University, Ministry of Health of Russian Federation, Moscow, Russia, 125412; Mental Health Research Center, Moscow, Russia, 117152
  • 50 Research Centre for Medical Genetics, Moscow, Russia
  • 51 Paediatrics Wah Medical College NUMS, Wah Cantonment, Punjab 44000, Pakistan
  • 52 University of Chicago Medicine, University of Chicago, Chicago, IL, USA
  • 53 Division of Genetics, Universidade Federal de Campina Grande, Campina Grande, Paraíba, Brazil
  • 54 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
  • 55 Department of Pediatric Neurology, Neo Clinic Children's Hospital, Jaipur 302019, India
  • 56 Department of Human Genetics, The University of Chicago, Illinois
  • 57 Department of Pediatric Neurology, Indira Gandhi Institute of Child Health, Bengaluru, India
  • 58 Department of Pediatric Neurology - Instituto de Medicina Integral Prof. Fernando Figueira (IMIP), Boa Vista, Recife, Brazil
  • 59 Oxford Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
  • 60 Clinical Genetics service, Northampton General Hospital, Northampton NN15BD, UK
  • 61 Department of Pediatrics, Fayoum University Hospitals, Fayoum, Egypt
  • 62 Instituto de Medicina Integral Prof. Fernando Figueira, Centro de Terapias Cetogênicas do IMIP, Recife PE, Brazil
  • 63 Department of Pediatric Gastroenterology Hepatology and Genetic diseases Children's Hospital and University of Child Health Sciences Lahore, Pakistan
  • 64 Al-Quds University, Jerusalem, Palestine
  • 65 PRCS hospital, Hebron, Palestine
  • 66 Department of Genetics, Hadassah Medical Center, Jerusalem, Israel; Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
  • 67 CENTOGENE GmbH, Am Strande 7, 18055 Rostock, Germany
  • 68 Mendelics Genomic Analysis, São Paulo, Brazil
  • 69 Hospices Civils de Lyon, Service de Génétique, Bron, France; Pathophysiology and Genetics of Neuron and Muscle (PGNM, UCBL - CNRS UMR5261 - INSERM U1315), Université Claude Bernard Lyon 1, Lyon, France
  • 70 Department of Neuropediatric, University Hospital of Lyon, Lyon, France
  • 71 Department of Pediatrics, Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN, USA
  • 72 GeneDx, Gaithersburg, MD 20877, USA
  • 73 Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX
  • 74 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA
  • 75 Clinical Research Centre, Sunway Medical Centre, Malaysia
  • 76 Department of Paediatric Neurology, Children Hospital and Institute of Child Health, Faisalabad, Pakistan
  • 77 Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
  • 78 Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, Sheffield, UK
  • 79 Birmingham Health Partners, West Midlands Regional Genetics Service, Birmingham Women's and Children's National Health Service (NHS) Foundation Trust, Birmingham, UK
  • 80 Division of Medical Genetics, 3Billion Inc, Seoul, South Korea
  • 81 Department of Pediatrics, Faculty of Medicine, Sohag University, Sohag, Egypt
  • 82 Laboratório Mendelics, Department of Genetic, São Paulo, Brazil
  • 83 Neurology Unit, Department of Pediatrics, Faculty of Medicine, Alexandria University, Egypt
  • 84 Genomic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  • 85 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA; Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX
  • 86 Murdoch Children's Research Institute and University of Melbourne of Melbourne Department of Paediatrics, Royal Children's Hospital, Melbourne, Australia
  • 87 Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusset's, USA
  • 88 Department of Medical Genetics, Next Generation Genetic Polyclinic, Mashhad, Iran; Molecular and Clinical Sciences Institute, St. George's, University of London, Cranmer Terrace, London SW17 0RE, UK; Innovative Medical Research Center, Mashhad Branch, Islamic Azad University, Mashhad, Iran
  • 89 CHU Sainte-Justine Research Center, Montreal, QC, Canada; Department of Pediatrics, Faculty of Medicine, Université de Montréal, Montreal, QC, Canada
  • 90 Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
  • 91 NIHR Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
  • 92 Department of Neurosciences, University of California, San Diego, La Jolla 92093, USA; Rady Children's Institute for Genomic Medicine, San Diego 92123, USA
  • 93 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
  • 94 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
  • 95 Department of Radiology, Neuroradiology Section, Kingston Health Sciences Centre, Queen's University Faculty of Health Sciences, Kingston, Ontario, Canada
  • 96 Department of Neuromuscular Diseases, University College London, Queen Square, Institute of Neurology, WC1N 3BG London, UK. Electronic address: r.maroofian@ucl.ac.uk
Genet Med, 2024 Sep 10.
PMID: 39275948 DOI: 10.1016/j.gim.2024.101251

Abstract

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 analysed 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 (GDD/ID), infantile intractable seizures, absent speech, autistic features, dystonia, and increased lethality. De novo monoallelic variants result in moderate-to-severe GDD/ID, absent speech, and autistic features, while seizures and dystonia were less frequently observed. Dysmorphic facial features and brain abnormalities, including hypoplastic corpus callosum, parenchymal volume loss/atrophy, are common findings in both groups. We reveal that in the nucleolus, ACTL6B plays a crucial role in ribosome biogenesis, in particular 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'.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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