Bi-allelic MED16 variants cause a MEDopathy with intellectual disability, motor delay, and craniofacial, cardiac, and limb malformations

Guillouet C. Agostini V. Baujat G. Cocciadiferro D. Pippucci T. Lesieur-Sebellin M. Georget M. Schatz U. Fauth C. Louie R.J. Rogers C. Davis J.M. Konstantopoulou V. Mayr J.A. Bouman A. Wilke M. VanNoy G.E. England E.M. Park K.L. Brown K. Saenz M. Novelli A. Digilio M.C. Mastromoro G. Rongioletti M.C.A. Piacentini G. Kaiyrzhanov R. Guliyeva S. Hasanova L. Shears D. Bhatnagar I. Stals K. Klaas O. Horvath J. Bouvagnet P. Witmer P.D. MacCarrick G. Cisarova K. Good J.-M. Gorokhova S. Boute O. Smol T. Bruel A.-L. Patat O. Broadbent J.R. Tan T.Y. Tan N.B. Lyonnet S. Busa T. Graziano C. Amiel J. Gordon C.T.
3 April 2025 Cell Press

American Journal of Human Genetics
2025 #112 Issue 4 829 - 845 pp.

The Mediator complex regulates protein-coding gene transcription by coordinating the interaction of upstream enhancers with the basal transcription machinery at the promoter. Pathogenic variants in Mediator subunits typically lead to neurodevelopmental or neurodegenerative disorders with variable clinical presentations, designated as MEDopathies. Here, we report the identification of 25 individuals from 18 families with bi-allelic MED16 variants who have a multiple congenital anomalies (MCAs)-intellectual disability syndrome. Intellectual disability, speech delay, and/or motor delay of variable severity were constant and associated with variable combinations of craniofacial defects (micro/retrognathia, cleft palate, and preauricular tags), anomalies of the extremities, and heart defects (predominantly tetralogy of Fallot). Visual impairment, deafness, and magnetic resonance imaging (MRI) abnormalities were also frequent. The 26 variants identified were comprised of eight predicted protein-truncating (three intragenic deletions, two frameshifts, and one nonsense and two essential splice site variants) and 18 missense or in-frame duplication variants affecting conserved residues, without clear correlation between phenotypic severity and variant type combination. Three-dimensional modeling indicated that the missense and duplication variants likely have a destabilizing effect on the structural elements of the protein. Immunofluorescence assays demonstrated protein mislocalization from the nucleus to the cytoplasm for 16 of the 17 variants studied. Homozygous mutant med16 zebrafish presented growth delay and increased mortality compared with wild-type fish, and Med16 knockout mice are preweaning lethal, highlighting the conserved requirement of MED16 for development. Overall, we describe an autosomal recessive MCAs-intellectual disability MEDopathy, emphasizing the importance of Mediator during neurodevelopment and suggesting that some tissues are particularly sensitive to the loss of certain subunits.

MED16 , Mediator complex , MEDopathies , multiple congenital anomalies-intellectual disability syndrome

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Laboratory of Embryology and Genetics of Malformations, INSERM UMR 1163, Institut Imagine, Université Paris Cité, Paris, France
Service de Médecine Génomique des Maladies Rares, Necker-Enfants Malades Hospital, AP-HP, Paris, France
Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Childrens Hospital, IRCCS, Rome, 00165, Italy
IRCCS Azienda Ospedaliero, Universitaria di Bologna, Bologna, Italy
Institute of Human Genetics, Medical University Innsbruck, Innsbruck, Austria
Greenwood Genetic Center, Greenwood, SC, United States
Department of Pediatrics and Adolescent Medicine, Austrian Newborn Screening, Medical University of Vienna, Vienna, 1090, Austria
University Childrens Hospital, Salzburger Landeskliniken (SALK), Paracelsus Medical University, Salzburg, 5020, Austria
Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, Netherlands
Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, United States
Departments of Pediatrics and Neurology, University of Colorado School of Medicine, Aurora, CO, United States
University of Colorado Anschutz Medical Campus, Aurora, CO, United States
Medical Genetics, Translational Pediatrics and Clinical Genetics Research Area, Bambino Gesù Childrens Hospital, IRCCS, Rome, 00146, Italy
Department of Laboratory Science, Ospedale Isola Tiberina - Gemelli Isola, Rome, Italy
Fetal and Neonatal Cardiology Unit, Ospedale Isola Tiberina - Gemelli Isola, Rome, Italy
Department of Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, United Kingdom
Department of Neurology, South Kazakhstan Medical Academy, Shymkent, Kazakhstan
MediClub Hospital, Baku, Azerbaijan
Caspian International Hospital, Baku, Azerbaijan
Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
Exeter Genomics Laboratory, Royal Devon University Healthcare NHS Foundation Trust, Exeter, United Kingdom
Institute for Human Genetics, University Hospital Muenster, Muenster, Germany
McKusick-Nathans Department of Genetic Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, United States
Division of Genetic Medicine, Lausanne University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland
Aix Marseille University, INSERM, MMG, U 1251, Marseille, 13005, France
Department of Medical Genetics, Timone Childrens Hospital, AP-HM, Marseille, 13005, France
University Lille, CHU Lille, ULR 7364 - RADEME - Maladies Rares du Développement Embryonnaire et du Métabolisme, Lille, 59000, France
INSERM UMR1231 Team GAD, University of Burgundy and Franche-Comté, Dijon, 21000, France
Functional Unit of Innovative Diagnosis for Rare Diseases, Dijon Bourgogne University Hospital, Dijon, 21000, France
Department of Medical Genetics, CHU Toulouse Purpan, Toulouse, France
Rare Disease Discovery Group, Murdoch Childrens Research Institute, Melbourne, VIC, Australia
Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia
Victorian Clinical Genetics Services, Melbourne, VIC, Australia
U.O. Genetica Medica, Azienda USL della Romagna, Ravenna, Italy
Institute of Human Genetics, Technical University of Munich, Munich, Germany
Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz, 8036, Austria
Département de Génétique, Laboratoire Eurofins Biomnis, Lyon, 69007, France
Centre Pluridisciplinaire de Diagnostic Prénatal, Hôpital MFME, CHU Martinique, Fort de France, France
University of Washington Center for Mendelian Genomics, Seattle, 98195, WA, United States

Laboratory of Embryology and Genetics of Malformations
Service de Médecine Génomique des Maladies Rares
Laboratory of Medical Genetics
IRCCS Azienda Ospedaliero
Institute of Human Genetics
Greenwood Genetic Center
Department of Pediatrics and Adolescent Medicine
University Childrens Hospital
Department of Clinical Genetics
Program in Medical and Population Genetics
Departments of Pediatrics and Neurology
University of Colorado Anschutz Medical Campus
Medical Genetics
Department of Laboratory Science
Fetal and Neonatal Cardiology Unit
Department of Neuromuscular Diseases
Department of Neurology
MediClub Hospital
Caspian International Hospital
Oxford Centre for Genomic Medicine
Exeter Genomics Laboratory
Institute for Human Genetics
McKusick-Nathans Department of Genetic Medicine
Division of Genetic Medicine
Aix Marseille University
Department of Medical Genetics
University Lille
INSERM UMR1231 Team GAD
Functional Unit of Innovative Diagnosis for Rare Diseases
Department of Medical Genetics
Rare Disease Discovery Group
Department of Paediatrics
Victorian Clinical Genetics Services
U.O. Genetica Medica
Institute of Human Genetics
Division of Oncology
Département de Génétique
Centre Pluridisciplinaire de Diagnostic Prénatal
University of Washington Center for Mendelian Genomics

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