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Clinical and Genetic Delineation of Autosomal Recessive and Dominant Actl6b-Related Developmental Brain Disorders Publisher Pubmed



Cali E1 ; Quirin T2 ; Rocca C1 ; Efthymiou S1 ; Riva A3 ; Marafi D4, 5 ; Zaki MS6 ; Suri M7, 8 ; Dominguez R9 ; Elbendary HM6 ; Alavi S1, 10 ; Abdelhamid MS11 ; Morsy H1, 12 ; Mauthem FT13, 14 Show All Authors
Authors
  1. Cali E1
  2. Quirin T2
  3. Rocca C1
  4. Efthymiou S1
  5. Riva A3
  6. Marafi D4, 5
  7. Zaki MS6
  8. Suri M7, 8
  9. Dominguez R9
  10. Elbendary HM6
  11. Alavi S1, 10
  12. Abdelhamid MS11
  13. Morsy H1, 12
  14. Mauthem FT13, 14
  15. Nizon M15, 16
  16. Tesner P17
  17. Ryba L17
  18. Zafar F18
  19. Rana N18
  20. Saadi NW19
  21. Firoozfar Z10
  22. Gencpinar P20
  23. Unay B21
  24. Ustun C21
  25. Bruel AL22, 23
  26. Coubes C24
  27. Stefanich J25
  28. Sezer O26
  29. Agolini E27
  30. Novelli A27
  31. Vasco G28
  32. Lettori D28
  33. Milh M29
  34. Villard L30
  35. Zeidler S31
  36. Opperman H32
  37. Strehlow V32
  38. Issa MY6
  39. El Khassab H33
  40. Chand P34
  41. Ibrahim S34
  42. Rashidinezhad A35, 36
  43. Miryounesi M37
  44. Larki P37
  45. Morrison J38
  46. Cristian I38
  47. Thiffault I39, 40, 41
  48. Bertsch NL42
  49. Noh GJ43
  50. Pappas J44, 45
  51. Moran E46
  52. Marinakis NM47
  53. Traegersynodinos J47
  54. Hosseini S48
  55. Abbaszadegan MR49
  56. Caumes R50
  57. Vissers LELM51, 52
  58. Neshatdoust M53
  59. Montazer Zohour M54
  60. El Fahime E55
  61. Canavati C56
  62. Kamal L56
  63. Kanaan M56
  64. Askander O57
  65. Voinova V58, 59
  66. Levchenko O60
  67. Haider S61
  68. Halbach SS62
  69. Elias Maia R63
  70. Mansoor S64, 65
  71. Jain V66
  72. Tawde S67
  73. Challa VSR68
  74. Gowda VK68
  75. Srinivasan VM68
  76. Victor LA69
  77. Pinerobanos B70
  78. Hague J71
  79. Elawady HA72
  80. Maria De Miranda Henriquessouza A73
  81. Cheema HA74
  82. Anjum MN74
  83. Idkaidak S75
  84. Alqarajeh F76
  85. Atawneh O76
  86. Morshaked H77
  87. Harel T77
  88. Zifarelli G78
  89. Bauer P78
  90. Kok F79
  91. Kitajima JP79
  92. Monteiro F79
  93. Josahkian J79
  94. Lesca G80, 81
  95. Chatron N80, 81
  96. Ville D82
  97. Murphy D83
  98. Neul JL84
  99. Mullegama SV85
  100. Begtrup A85
  101. Herman I86
  102. Mitani T4
  103. Posey JE4
  104. Tay CG87
  105. Javed I88
  106. Carr L89
  107. Kanani F90
  108. Beecroft F90
  109. Hane L91
  110. Abdelkreem E92
  111. Macek M17
  112. Bispo L93
  113. Elmaksoud MA94
  114. Hashemigorji F95
  115. Pehlivan D4, 86
  116. Amor DJ96
  117. Jamra RA32
  118. Chung WK97
  119. Ghayoor Karimiani E98, 99, 100
  120. Campeau PM101, 102
  121. Alkuraya FS103
  122. Pagnamenta AT104
  123. Gleeson JG105, 106
  124. Lupski JR4, 107, 108
  125. Striano P3, 109
  126. Morenodeluca A110
  127. Lafontaine DLJ2
  128. Houlden H1
  129. Maroofian R1
Show Affiliations
Authors Affiliations
  1. 1. Department of Neuromuscular Diseases, University College London, Queen Square, Institute of Neurology, London, United Kingdom
  2. 2. RNA Molecular Biology, Fonds de la Recherche Scientifique (F.R.S./FNRS), Universite libre de Bruxelles (ULB), Biopark campus, Gosselies, Belgium
  3. 3. Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy
  4. 4. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
  5. 5. Department of Pediatrics, Faculty of Medicine, Kuwait University, Safat, Kuwait
  6. 6. Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt
  7. 7. UK National Paediatric Ataxia Telangiectasia Clinic, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom
  8. 8. Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom
  9. 9. Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
  10. 10. Palindrome, Isfahan, Iran
  11. 11. Medical Molecular Genetics Department, Human Genetics and Genome Research Institute, National Research Centre Cairo, Egypt
  12. 12. Human Genetics Department, Medical Research Institute, Alexandria University, Egypt
  13. 13. Unite Fonctionnelle 6254 d'Innovation en Diagnostique Genomique des Maladies Rares, Pole de Biologie, CHU Dijon Bourgogne, Dijon, France
  14. 14. INSERM UMR1231 GAD, Dijon, France
  15. 15. Service de genetique medicale, CHU de Nantes, Nantes, France
  16. 16. Institut du thorax, INSERM, CNRS, UNIV Nantes, Nantes, France
  17. 17. Department of Biology and Medical Genetics, 2nd Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic
  18. 18. Department of Paediatric Neurology, Children's Hospital and Institute of Child Health, Multan, Pakistan
  19. 19. College of Medicine/University of Baghdad, Unit of Pediatric Neurology, Children Welfare Teaching Hospital, Baghdad, Iraq
  20. 20. Izmir Katip Celebi University Tepecik Training and Research Department of Pediatric Neurology, Izmir, Turkiye
  21. 21. University of Health Sciences, Gulhane Faculty of Medicine, Department of Child Neurology, Ankara, Turkiye
  22. 22. Unite Fontctionnelle d'Innovation diagnostiques des maladies rares, FHU TRANSLAD, CHU Dijon Bourgogne, Dijon, France
  23. 23. INSERM-Universite de Bourgogne UMR1231 GAD “Genetique des Anomalies du Developpement”, Dijon, France
  24. 24. Departement de Genetique Medicale, Maladies rares et Medecine Personnalisee, et Centre de Reference Anomalies du Developpement et Syndromes Malformatifs, CHRU de Montpellier, Montpellier, France
  25. 25. Genetic Center, Akron Children's Hospital, Akron, OH, United States
  26. 26. Department of Medical Genetics, Samsun University, Faculty of Medicine, Samsun, Turkiye
  27. 27. Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesu Children Hospital, IRCCS, Rome, Italy
  28. 28. Department of Neurosciences, Unit of Neurorehabilitation, Bambino Gesu Children's Hospital, IRCCS, Rome, Italy
  29. 29. Aix-Marseille Univ, APHM, department of Pediatrics Neurology. Timone children Hospital. Marseille, France
  30. 30. Aix Marseille Univ, Inserm, MMG, Marseille, France, Service de Genetique Medicale, AP-HM, Hopital de La Timone, France, Marseille, France
  31. 31. Department of Clinical Genetics, Erasmus MC, Rotterdam, Netherlands
  32. 32. Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
  33. 33. Sulaiman Al Habib Hospital - Olaya Medical Complex-Riyadh, Saudi Arabia
  34. 34. Department of Paediatric and Child Health, Aga Khan University Hospital, Karachi, Pakistan
  35. 35. Maternal, Fetal and Neonatal Research Center, Family Health Research Institute, Tehran University of Medical Sciences, Tehran, Iran
  36. 36. Genetics Ward, Yas Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
  37. 37. Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  38. 38. Division of Genetics, Arnold Palmer Hospital for Children, Orlando Health, Orlando, FL, United States
  39. 39. Genomic Medicine Center, Children's Mercy Hospital, Kansas City, MO, United States
  40. 40. Kansas City School of Medicine, University of Missouri, Kansas City, MO, United States
  41. 41. Department of Pathology and Laboratory Medicine, Children's Mercy Hospital, Kansas City, MO, United States
  42. 42. The Community Health Clinic, Shipshewana, IN, United States
  43. 43. Department of Genetics, Southern California Permanente Medical Group, Fontana, CA, United States
  44. 44. Clinical Genetic Services, Department of Pediatrics, NYU Grossman School of Medicine, New York, NY, United States
  45. 45. Clinical Genetics, NYU Orthopedic Hospital, New York, NY, United States
  46. 46. Clinical Genetics, Center for Children, Hassenfeld Children's Hospital, New York University, New York, NY, United States
  47. 47. Laboratory of Medical Genetics, Medical School, National and Kapodistrian University of Athens, St. Sophia's Children's Hospital, Athens, Greece
  48. 48. Pardis Pathobiology and Genetics Laboratory, Mashhad, Iran
  49. 49. Department of Medical Genetics and Molecular Medicine, School of Medicine, Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
  50. 50. Service de Genetique Clinique, CHU Lille, Lille, France
  51. 51. Department of Human Genetics, Radboudumc University Medical Center, Nijmegen, Netherlands
  52. 52. Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, Netherlands
  53. 53. Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
  54. 54. Genetics of Non-Communicable Disease Research Center, Zahedan University of Medical Sciences, Zahedan, Iran
  55. 55. Centre Mohamed VI for Research and Innovation (CM6RI) and University Mohamed VI for Health Science (UM6SS), Benguerir, Morocco
  56. 56. Molecular Genetics Laboratory, Istishari Arab Hospital, Ramallah, Palestine
  57. 57. Faculty of Medical Sciences, Mohammed 6 Polytechnic University of Benguerir, Ben Guerir, Morocco
  58. 58. Veltischev Research and Clinical Institute for Pediatrics of the Pirogov, Russian National Research Medical University, Ministry of Health of Russian Federation, Moscow, Russian Federation
  59. 59. Mental Health Research Center, Moscow, Russian Federation
  60. 60. Research Centre for Medical Genetics, Moscow, Russian Federation
  61. 61. Paediatrics Wah Medical College NUMS, Punjab, Wah Cantonment, Pakistan
  62. 62. University of Chicago Medicine, University of Chicago, Chicago, IL, United States
  63. 63. Department of Paediatrics and Genetics, Universidade Federal de Paraiba, Paraiba, Joao Pessoa, Brazil
  64. 64. Cellular, Molecular and Genetics Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
  65. 65. Medical Genetics Research Center of Genome, Isfahan University of Medical Sciences, Isfahan, Iran
  66. 66. Department of Pediatric Neurology, Neo Clinic Children's Hospital, Jaipur, India
  67. 67. Department of Human Genetics, The University of Chicago, Illinois, United States
  68. 68. Department of Pediatric Neurology, Indira Gandhi Institute of Child Health, Bengaluru, India
  69. 69. Department of Pediatric Neurology - Instituto de Medicina Integral Prof. Fernando Figueira (IMIP), Boa Vista, Recife, Brazil
  70. 70. Oxford Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
  71. 71. Clinical Genetics service, Northampton General Hospital, Northampton, United Kingdom
  72. 72. Department of Pediatrics, Fayoum University Hospitals, Fayoum, Egypt
  73. 73. Instituto de Medicina Integral Prof. Fernando Figueira, Centro de Terapias Cetogenicas do IMIP, Recife PE, Brazil
  74. 74. Department of Pediatric Gastroenterology Hepatology and Genetic diseases Children's Hospital and University of Child Health Sciences Lahore, Pakistan
  75. 75. Al-Quds University, Jerusalem, Palestine
  76. 76. PRCS hospital, Hebron, Palestine
  77. 77. Department of Genetics, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
  78. 78. CENTOGENE GmbH, Rostock, Germany
  79. 79. Mendelics Genomic Analysis, Sao Paulo, Brazil
  80. 80. Hospices Civils de Lyon, Service de Genetique, Bron, France
  81. 81. Pathophysiology and Genetics of Neuron and Muscle (PGNM, UCBL - CNRS UMR5261 - INSERM U1315), Universite Claude Bernard Lyon 1, Lyon, France
  82. 82. Department of Neuropediatric, University Hospital of Lyon, Lyon, France
  83. 83. Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom
  84. 84. Department of Pediatrics, Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN, United States
  85. 85. GeneDx, Gaithersburg, MD, United States
  86. 86. Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
  87. 87. Clinical Research Centre, Sunway Medical Centre, Malaysia
  88. 88. Department of Paediatric Neurology, Children Hospital and Institute of Child Health, Faisalabad, Pakistan
  89. 89. Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
  90. 90. West Midlands Clinical Genetics Service, Birmingham Women's Hospital, Birmingham, United Kingdom
  91. 91. Division of Medical Genetics, 3billion, Inc, Seoul, South Korea
  92. 92. Department of Pediatrics, Faculty of Medicine, Sohag University, Sohag, Egypt
  93. 93. Laboratorio Mendelics, Department of Genetic, Sao Paulo, Brazil
  94. 94. Neurology Unit, Department of Pediatrics, Faculty of Medicine, Alexandria University, Egypt
  95. 95. Genomic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  96. 96. Department of Paediatrics, Murdoch Children's Research Institute and University of Melbourne, Royal Children's Hospital, Melbourne, Australia
  97. 97. Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA, United States
  98. 98. Department of Medical Genetics, Next Generation Genetic Polyclinic, Mashhad, Iran
  99. 99. Molecular and Clinical Sciences Institute, St. George's, University of London, Cranmer Terrace, London, United Kingdom
  100. 100. Innovative Medical Research Center, Mashhad Branch, Islamic Azad University, Mashhad, Iran
  101. 101. CHU Sainte-Justine Research Center, Montreal, QC, Canada
  102. 102. Department of Pediatrics, Faculty of Medicine, Universite de Montreal, Montreal, QC, Canada
  103. 103. Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
  104. 104. NIHR Biomedical Research Centre, Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
  105. 105. Department of Neurosciences, University of California, San Diego, La Jolla, CA, United States
  106. 106. Rady Children's Institute for Genomic Medicine, San Diego, CA, United States
  107. 107. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, United States
  108. 108. Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
  109. 109. Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genova, Italy
  110. 110. Department of Radiology, Neuroradiology Section, Kingston Health Sciences Centre, Queen's University Faculty of Health Sciences, Kingston, ON, Canada

Source: Genetics in Medicine Published:2025


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 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.” © 2024 The Authors