Evidence map›Paper›PMID 40081376›Full record

ArticleAmerican journal of human genetics2025

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

Charlotte Guillouet, Valeria Agostini, Geneviève Baujat, Dario Cocciadiferro, Tommaso Pippucci, Marion Lesieur-Sebellin, Mathieu Georget, Ulrich Schatz, Christine Fauth, Raymond J Louie and 43 more

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Article in American journal of human genetics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

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0cells of the map it votes in
3citing papers in PubMed
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1 · What the graph read from it

What it found

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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

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3 · Its place in the literature

Who cites it

3 citing papers in PubMed.

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4 · The record

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PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

53 authors.

Charlotte GuillouetLaboratory of Embryology and Genetics of Malformations, INSERM UMR 1163, Institut Imagine, Université Paris Cité, Paris, France.
Valeria AgostiniLaboratory of Embryology and Genetics of Malformations, INSERM UMR 1163, Institut Imagine, Université Paris Cité, Paris, France.
Geneviève BaujatService de Médecine Génomique des Maladies Rares, Necker-Enfants Malades Hospital, AP-HP, Paris, France.
Dario CocciadiferroLaboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy.
Tommaso PippucciIRCCS Azienda Ospedaliero, Universitaria di Bologna, Bologna, Italy.
Marion Lesieur-SebellinLaboratory of Embryology and Genetics of Malformations, INSERM UMR 1163, Institut Imagine, Université Paris Cité, Paris, France.
Mathieu GeorgetLaboratory of Embryology and Genetics of Malformations, INSERM UMR 1163, Institut Imagine, Université Paris Cité, Paris, France.
Ulrich SchatzInstitute of Human Genetics, Medical University Innsbruck, Innsbruck, Austria; Institute of Human Genetics, Technical University of Munich, Munich, Germany.
Christine FauthInstitute of Human Genetics, Medical University Innsbruck, Innsbruck, Austria.
Raymond J LouieGreenwood Genetic Center, Greenwood, SC, USA.
Curtis RogersGreenwood Genetic Center, Greenwood, SC, USA.
Jessica M DavisGreenwood Genetic Center, Greenwood, SC, USA.
Vassiliki KonstantopoulouDepartment of Pediatrics and Adolescent Medicine, Austrian Newborn Screening, Medical University of Vienna, 1090 Vienna, Austria.
Johannes A MayrUniversity Children's Hospital, Salzburger Landeskliniken (SALK), Paracelsus Medical University, 5020 Salzburg, Austria.
Arjan BoumanDepartment of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands.
Martina WilkeDepartment of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands.
Grace E VanNoyProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Eleina M EnglandProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Kristen L ParkDepartments of Pediatrics and Neurology, University of Colorado School of Medicine, Aurora, CO, USA.
Kathleen BrownUniversity of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Margarita SaenzUniversity of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Antonio NovelliLaboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy.
Maria Cristina DigilioMedical Genetics, Translational Pediatrics and Clinical Genetics Research Area, Bambino Gesù Children's Hospital, IRCCS, 00146 Rome, Italy.
Gioia MastromoroDepartment of Laboratory Science, Ospedale Isola Tiberina - Gemelli Isola, Rome, Italy.
Mauro Ciro Antonio RongiolettiDepartment of Laboratory Science, Ospedale Isola Tiberina - Gemelli Isola, Rome, Italy.
Gerardo PiacentiniFetal and Neonatal Cardiology Unit, Ospedale Isola Tiberina - Gemelli Isola, Rome, Italy.
Rauan KaiyrzhanovDepartment of Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK; Department of Neurology, South Kazakhstan Medical Academy, Shymkent, Kazakhstan.
Sughra GuliyevaMediClub Hospital, Baku, Azerbaijan.
Lala HasanovaCaspian International Hospital, Baku, Azerbaijan.
Deborah ShearsOxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
Ishita BhatnagarOxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
Karen StalsExeter Genomics Laboratory, Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK.
Oliver KlaasInstitute for Human Genetics, University Hospital Muenster, Muenster, Germany.
Judit HorvathInstitute for Human Genetics, University Hospital Muenster, Muenster, Germany.
University of Washington Center for Mendelian GenomicsUniversity of Washington Center for Mendelian Genomics, Seattle, WA 98195, USA.
Patrice BouvagnetDépartement de Génétique, Laboratoire Eurofins Biomnis, 69007 Lyon, France; Centre Pluridisciplinaire de Diagnostic Prénatal, Hôpital MFME, CHU Martinique, Fort de France, France.
P Dane WitmerMcKusick-Nathans Department of Genetic Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Gretchen MacCarrickMcKusick-Nathans Department of Genetic Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Katarina CisarovaDivision of Oncology, Department of Internal Medicine, Medical University of Graz, 8036 Graz, Austria.
Jean-Marc GoodDivision of Genetic Medicine, Lausanne University Hospital (CHUV) and University of Lausanne, Lausanne, Switzerland.
Svetlana GorokhovaAix Marseille University, INSERM, MMG, U 1251, 13005 Marseille, France; Department of Medical Genetics, Timone Children's Hospital, AP-HM, 13005 Marseille, France.
Odile BouteUniversity Lille, CHU Lille, ULR 7364 - RADEME - Maladies Rares du Développement Embryonnaire et du Métabolisme, 59000 Lille, France.
Thomas SmolUniversity Lille, CHU Lille, ULR 7364 - RADEME - Maladies Rares du Développement Embryonnaire et du Métabolisme, 59000 Lille, France.
Ange-Line BruelINSERM UMR1231 Team GAD, University of Burgundy and Franche-Comté, 21000 Dijon, France; Functional Unit of Innovative Diagnosis for Rare Diseases, Dijon Bourgogne University Hospital, 21000 Dijon, France.
Olivier PatatDepartment of Medical Genetics, CHU Toulouse Purpan, Toulouse, France.
Julia R BroadbentRare Disease Discovery Group, Murdoch Children's Research Institute, Melbourne, VIC, Australia.
Tiong Y TanRare Disease Discovery Group, Murdoch Children's Research Institute, Melbourne, VIC, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia; Victorian Clinical Genetics Services, Melbourne, VIC, Australia.
Natalie B TanVictorian Clinical Genetics Services, Melbourne, VIC, Australia.
Stanislas LyonnetLaboratory 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.
Tiffany BusaDepartment of Medical Genetics, Timone Children's Hospital, AP-HM, 13005 Marseille, France.
Claudio GrazianoU.O. Genetica Medica, Azienda USL della Romagna, Ravenna, Italy.
Jeanne AmielLaboratory 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.
Christopher T GordonLaboratory of Embryology and Genetics of Malformations, INSERM UMR 1163, Institut Imagine, Université Paris Cité, Paris, France. Electronic address: chris.gordon@inserm.fr.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

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.

Indexed as

Abnormalities, MultipleCraniofacial AbnormalitiesDevelopmental DisabilitiesHeart Defects, CongenitalIntellectual DisabilityMediator ComplexAllelesAnimalsChildChild, PreschoolFemaleHumansMaleMiceMutationPedigreeMediator ComplexMED16Mediator complexMEDopathiesmultiple congenital anomalies-intellectual disability syndrome

Identifiers

PMID40081376
PMCPMC12081314

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