BRAT1–related disorders: phenotypic spectrum and phenotype-genotype correlations from 97 patients

Engel C. Valence S. Delplancq G. Maroofian R. Accogli A. Agolini E. Alkuraya F.S. Baglioni V. Bagnasco I. Becmeur-Lefebvre M. Bertini E. Borggraefe I. Brischoux-Boucher E. Bruel A.-L. Brusco A. Bubshait D.K. Cabrol C. Cilio M.R. Cornet M.-C. Coubes C. Danhaive O. Delague V. Denommé-Pichon A.-S. Di Giacomo M.C. Doco-Fenzy M. Engels H. Cremer K. Gérard M. Gleeson J.G. Heron D. Goffeney J. Guimier A. Harms F.L. Houlden H. Iacomino M. Kaiyrzhanov R. Kamien B. Karimiani E.G. Kraus D. Kuentz P. Kutsche K. Lederer D. Massingham L. Mignot C. Morris-Rosendahl D. Nagarajan L. Odent S. Ormières C. Partlow J.N. Pasquier L. Penney L. Philippe C. Piccolo G. Poulton C. Putoux A. Rio M. Rougeot C. Salpietro V. Scheffer I. Schneider A. Srivastava S. Straussberg R. Striano P. Valente E.M. Venot P. Villard L. Vitobello A. Wagner J. Wagner M. Zaki M.S. Zara F. Lesca G. Yassaee V.R. Miryounesi M. Hashemi-Gorji F. Beiraghi M. Ashrafzadeh F. Galehdari H. Walsh C. Novelli A. Tacke M. Sadykova D. Maidyrov Y. Koneev K. Shashkin C. Capra V. Zamani M. Van Maldergem L. Burglen L. Piard J.
September 2023 Springer Nature

European Journal of Human Genetics
2023 #31 Issue 9 1023 - 1031 pp.

BRAT1 biallelic variants are associated with rigidity and multifocal seizure syndrome, lethal neonatal (RMFSL), and neurodevelopmental disorder associating cerebellar atrophy with or without seizures syndrome (NEDCAS). To date, forty individuals have been reported in the literature. We collected clinical and molecular data from 57 additional cases allowing us to study a large cohort of 97 individuals and draw phenotype-genotype correlations. Fifty-nine individuals presented with BRAT1-related RMFSL phenotype. Most of them had no psychomotor acquisition (100%), epilepsy (100%), microcephaly (91%), limb rigidity (93%), and died prematurely (93%). Thirty-eight individuals presented a non-lethal phenotype of BRAT1-related NEDCAS phenotype. Seventy-six percent of the patients in this group were able to walk and 68% were able to say at least a few words. Most of them had cerebellar ataxia (82%), axial hypotonia (79%) and cerebellar atrophy (100%). Genotype-phenotype correlations in our cohort revealed that biallelic nonsense, frameshift or inframe deletion/insertion variants result in the severe BRAT1-related RMFSL phenotype (46/46; 100%). In contrast, genotypes with at least one missense were more likely associated with NEDCAS (28/34; 82%). The phenotype of patients carrying splice variants was variable: 41% presented with RMFSL (7/17) and 59% with NEDCAS (10/17).

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Centre de Génétique Humaine, Centre Hospitalier Régional Universitaire, Université de Franche-Comté, Besançon, France
Service de Neurologie Pédiatrique, Hôpital Armand Trousseau, APHP Sorbonne Université, Paris, France
Department of Neuromuscular Diseases UCL Queen Square Institute of Neurology, University College London, London, United Kingdom
Department of Specialized Medicine, Division of Medical Genetics, McGill University Health Centre, Montreal, QC, Canada
Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy
Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
Department of Human Neurosciences, Institute of Child and Adolescent Neuropsychiatry, Sapienza University of Rome, Rome, Italy
Division of Neuropsychiatry, Epilepsy Center for Children, Martini Hospital, Turin, 10141, Italy
Service de Génétique Clinique, CHR d’Orléans, Orléans, France
Unit of Neuromuscular and Neurodegenerative Disorders, Department of Neurosciences, Bambino Gesù Children’s Hospital IRCCS, Rome, Italy
Department of Pediatric Neurology, Developmental Medicine and Social Pediatrics, University of Munich, Munich, 80337, Germany
UMR 1231 GAD, Inserm, Université de Bourgogne Franche Comté, Dijon, France
Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France
Department of Medical Sciences, University of Torino, Turin, 10126, Italy
Department of Pediatrics, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
Department of Pediatrics, Division of Pediatric Neurology Saint-Luc University Hospital, and Institute of Neuroscience (IoNS), Catholic University of Louvain, Brussels, Belgium
Department of Pediatrics, Division of Neonatology, University of California San Francisco, San Francisco, CA, United States
Département de Génétique Médicale, Maladies Rares et Médecine Personnalisée, Hôpital Arnaud de Villeneuve, CHU de Montpellier, Montpellier, France
Division of Neonatology, Saint-Luc university Hospital, and Institut of Clinical and Experimental Research (IREC), Bruxelles, Belgium
Aix Marseille Univ, INSERM, Marseille Medical Genetics Center, MMG, Marseille, France
Medical Genetics Service and Laboratory of Cytogenetics, SIC Anatomia Patologica, “San Carlo” Hospital, Potenza, 85100, Italy
CHU Reims, Service de Génétique, Reims, France
CHU de Nantes, service de génétique médicale, Nantes, France
L’institut du thorax, INSERM, UNIV Nantes, Nantes, France
Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany
Clinical Genetics, Côte de Nacre University Hospital Center, Caen, France
University of California San Diego, Department of Neurosciences, Rady Children’s Institute for Genomic Medicine, San Diego, 92037, CA, United States
Department of Genetics, Pitié-Salpêtrière Hospital, AP-HP, Sorbonne University, Paris, France
Service de neuropédiatrie, Centre Hospitalier Régional Universitaire, Université de Franche-Comté, Besançon, France
Service de Médecine Génomique des Maladies Rares, Hôpital Necker Enfants Malades, Institut Imagine et Université Paris-Cité, Paris, France
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
Unit of Medical Genetics, IRCCS Instituto Giannina Gaslini, Genova, Italy
Genetic Services of Western Australia, King Edward Memorial Hospital, Perth, 6008, WA, Australia
Department of Molecular Genetics, Next Generation Genetic Polyclinic, Mashhad, Iran
Molecular and Clinical Sciences Institute, St. George’s, University of London, Cranmer Terrace, London, SW17 0RE, United Kingdom
Department of Neurology, Schneider Children’s Medical Center of Israel, Petah Tiqva, Israel
Sackler Faculty of Medicine, Tel Aviv, Tel Aviv University, 6997801, Israel
Oncobiologie Génétique Bioinformatique, PCBio, CHU Besançon, Besançon, France
Institute for Pathology and Genetics, Gosselies, 6040, Belgium
Division of Medical Genetics, Department of Pediatrics, Hasbro Children’s Hospital, Providence, RI, United States
APHP, Sorbonne Université, Département de Génétique, Paris, France
Centre de Référence Déficiences Intellectuelles de Causes Rares, GH Pitié-Salpêtrière/Hôpital Armand Trousseau, Paris, France
Clinical Genetics and Genomics, Royal Brompton and Harefield NHS Foundation Trust, London, United Kingdom
NHLI, Imperial College London, London, United Kingdom
Department of Neurology, Perth Children’s Hospital, Nedlands, WA, Australia
University of Western Australia, Nedlands, WA, Australia
Service de Génétique Clinique, Centre Référence “Déficiences Intellectuelles de causes rares” (CRDI), Centre Référence Anomalies du développement (CLAD-Ouest), CHU Rennes, Univ Rennes, Rennes, France
Division of Genetics and Genomics and Howard Hughes Medical Institute, Boston Children’s Hospital, Boston, MA, United States
Department of Pediatrics, IWK Health Centre, Dalhousie University, Halifax, NS, Canada
UOSD Neuro-oncology, IRCCS Giannina Gaslini, Genova, Italy
Hospices Civils de Lyon, Service de Génétique, Bron, France
Équipe GENDEV, Centre de Recherche en Neurosciences de Lyon, INSERM U1028 CNRS UMR5292, Université Claude Bernard Lyon 1, Lyon, France
Hôpital Femme Mère Enfant, Service de Neuropédiatrie, Bron, France
IRCCS Giannina Gaslini Institute, Genova, Italy
Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genova, Genova, Italy
Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, VIC, Australia
Royal Children’s Hospital, Florey Institute and Murdoch Children’s Research Institute, Melbourne, VIC, Australia
Department of Neurology, Boston Children’s Hospital, Boston, MA, United States
Department of Molecular Medicine, University of Pavia, Pavia, Italy
Neurogenetics Research Center, IRCCS Mondino Foundation, Pavia, Italy
Neonatal Intensive Care Unit, Institut Alix de Champagne, Reims, France
Département de Génétique Médicale, AP-HM, Hôpital d’Enfants de La Timone, Marseille, France
Institute for Neurogenomics, Helmholtz Center Munich, Neuherberg, Germany
Institute of Human Genetics, School of Medicine, Technical University Munich, Munich, Germany
Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt
Pathophysiology and Genetics of Neuron and Muscle (PGNM, UCBL – CNRS UMR5261 – INSERM U1315), Université Claude Bernard Lyon 1, Lyon, France
Genomic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Department of Medical Genetics, Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Department of Pediatrics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran
Astana Medical University, Nur-Sultan, Kazakhstan
S. D. Asfendiyarov Kazakh National Medical University Almaty, Almaty, Kazakhstan
Department of Neurology and Neurosurgery, Asfendiyarov Kazakh National Medical University, Almaty, 050000, Kazakhstan
Department of Neurology, The International Institute of Postraduate Education, Almaty, Kazakhstan
Centre de Référence des Malformations et Maladies Congénitales du Cervelet, Département de Génétique, AP-HP, Sorbonne Université, Hôpital Trousseau, Paris, France

Centre de Génétique Humaine
Service de Neurologie Pédiatrique
Department of Neuromuscular Diseases UCL Queen Square Institute of Neurology
Department of Specialized Medicine
Laboratory of Medical Genetics
Department of Translational Genomics
Department of Human Neurosciences
Division of Neuropsychiatry
Service de Génétique Clinique
Unit of Neuromuscular and Neurodegenerative Disorders
Department of Pediatric Neurology
UMR 1231 GAD
Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares
Department of Medical Sciences
Department of Pediatrics
Department of Pediatrics
Department of Pediatrics
Département de Génétique Médicale
Division of Neonatology
Aix Marseille Univ
Medical Genetics Service and Laboratory of Cytogenetics
CHU Reims
CHU de Nantes
L’institut du thorax
Institute of Human Genetics
Clinical Genetics
University of California San Diego
Department of Genetics
Service de neuropédiatrie
Service de Médecine Génomique des Maladies Rares
Institute of Human Genetics
Unit of Medical Genetics
Genetic Services of Western Australia
Department of Molecular Genetics
Molecular and Clinical Sciences Institute
Department of Neurology
Sackler Faculty of Medicine
Oncobiologie Génétique Bioinformatique
Institute for Pathology and Genetics
Division of Medical Genetics
APHP
Centre de Référence Déficiences Intellectuelles de Causes Rares
Clinical Genetics and Genomics
NHLI
Department of Neurology
University of Western Australia
Service de Génétique Clinique
Division of Genetics and Genomics and Howard Hughes Medical Institute
Department of Pediatrics
UOSD Neuro-oncology
Hospices Civils de Lyon
Équipe GENDEV
Hôpital Femme Mère Enfant
IRCCS Giannina Gaslini Institute
Department of Neurosciences
Department of Medicine
Royal Children’s Hospital
Department of Neurology
Department of Molecular Medicine
Neurogenetics Research Center
Neonatal Intensive Care Unit
Département de Génétique Médicale
Institute for Neurogenomics
Institute of Human Genetics
Clinical Genetics Department
Pathophysiology and Genetics of Neuron and Muscle (PGNM
Genomic Research Center
Department of Medical Genetics
Department of Pediatrics
Department of Biology
Astana Medical University
S. D. Asfendiyarov Kazakh National Medical University Almaty
Department of Neurology and Neurosurgery
Department of Neurology
Centre de Référence des Malformations et Maladies Congénitales du Cervelet

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