Mapping variants in thyroid hormone transporter MCT8 to disease severity by genomic, phenotypic, functional, structural and deep learning integration.

Journal: Nature communications

Volume: 16

Issue: 1

Year of Publication: 2025

Affiliated Institutions:  Academic Center for Thyroid Diseases, Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands. Department of Clinical Biochemistry (CIBICI-CONICET), Faculty of Chemical Sciences, National University of Córdoba, Córdoba, Argentina. Department of Systems Biology, Harvard Medical School, Boston, MA, USA. Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands. Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA, USA. Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany. Division of Pediatric Endocrinology, Faculty of Medicine, Dokuz Eylul University, İzmir, Turkey. Department of Paediatrics, Division of Endocrinology, Erasmus Medical Centre -Sophia Children's Hospital, Rotterdam, The Netherlands. Department of Paediatric Neurology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. Regional Genetics Program, Children's Hospital of Eastern Ontario and Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, ON, Canada. Centrul Medical Dr. Bacos Cosma, Timisoara, Romania. University of Louisville, Louisville, KY, USA. Carol Davila University of Medicine, Department of Clinical Neurosciences, Paediatric Neurology Discipline II, Bucharest, Romania. Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA, USA. Diagnostic Laboratory for Endocrinology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands. Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesu' Children's Research Hospital IRCCS, Rome, Italy. Department of Pediatrics, Division of Pediatric Cardiology, Erasmus Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands. Department of Translational Medicine, Federico II University, , Naples, Italy. Gottfried Preyer's Children Hospital, Vienna, Austria. Research Area for Innovative Therapies in Endocrinopathies, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy. Department of Neurology, Clinica Meds, School of Medicine, Universidad Finis Terrae, Santiago, Chile. Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, UK. Division of Endocrinology, The Hospital for Sick Children and Department of Paediatrics, University of Toronto, Toronto, MG ×, Canada. East Kent Hospitals University NHS Foundation Trust, Ashford, UK. Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center (Radboudumc), Nijmegen, The Netherlands. Department of Toxicogenomics, Unit Clinical Genomics, Maastricht University, MHeNs School for Mental Health and Neuroscience, Maastricht, The Netherlands. Department of Pediatric Endocrinology and Diabetology, University Hospital, Angers, France. John Hunter Children's Hospital, Hunter Medical Research Institute, University of Newcastle, New Lambton Heights, Australia. Department of Paediatric Neurology, Clinical Research Facility, Lancashire Teaching Hospitals NHS Trust, Lancashire, UK. Genomics Institute Mary Bridge Children's Hospital, MultiCare Health System, Tacoma, WA, USA. The Department of Oncology and Metabolism, The University of Sheffield, Western Bank, Sheffield, S, TH, UK. Division of Paediatric Radiology, Erasmus Medical Centre - Sophia's Children Hospital, Rotterdam, The Netherlands. Medanta Superspeciality Hospital, Indore, India. Department of Neuropediatrics, University Children's Hospital, University of Zurich, Zurich, Switzerland. Department of Diabetes and Endocrinology, Women's and Children's Hospital, North Adelaide, , South Australia, Australia. Plymouth Hospitals NHS Trust, Plymouth, UK. UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA. Department of Endocrinology, St. John's Medical College Hospital, Bengaluru, India. Centre for Endocrinology, William Harvey Research institute, Queen Mary University of London, London, UK. Department of Pediatrics, Division of Pediatric Endocrinology, University of Alabama at Birmingham, Birmingham, AL, USA. Pediatric Center, Semmelweis University Budapest, Budapest, Hungary. Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA. Department of Endocrinology & Diabetes, Queensland Children's Hospital, South Brisbane, Queensland, Australia. Department of Pediatrics, Hematology and Oncology, Medical University of Gdańsk, Gdańsk, Poland. Department of Paediatric Neurology, Erasmus Medical Centre, Rotterdam, The Netherlands. Division of Pediatric Endocrinology and Diabetology and Children's Research Center, University Children's Hospital, University of Zurich, Zurich, Switzerland. Institute of Experimental Paediatric Endocrinology, Charité-Universitätsmedizin Berlin, Berlin, Germany. Department of Paediatric Endocrinology, SRCC Children's Hospital, Mumbai, India. Institute of Clinical Chemistry and Department of Pediatrics, Inselspital, University Hospital Bern, Bern, Switzerland. Department of Pediatrics, Doernbecher Children's Hospital, Oregon Health & Sciences University, Portland, OR, USA. Department of Paediatrics, Second Faculty of Medicine, Charles University, University Hospital Motol, Prague, Czech Republic. Division of Neuropediatrics and Muscular Disorders, Department of Pediatrics and Adolescent Medicine, University Hospital Freiburg, Freiburg, Germany. Teaching Hospital of Universidade Federal de Pelotas, Pelotas, Brazil. National Reference Center for Rare Diseases, Faculdade de Medicina de São José do Rio Preto, São José do Rio Preto, Brazil. Department of Child Neurology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. Institute of Maternal and Child Research, University of Chile, Santiago, Chile, Department of Pediatrics, Clinica Las Condes, Santiago, Chile. Pediatric Endocrinology Group, Sabara Children's Hospital, São Paulo, Brazil. Heim Pal National Pediatric Institute, Budapest, Hungary. Department of Paediatric Endocrinology and Genetics, Children's Hospital, Toulouse University Hospital, Toulouse, France. Endocrinology and Diabetology Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. Department of Paediatrics, Christian Medical College, Vellore, India. Paediatric Endocrinology, Diabetology and Gynaecology, Department, Necker Children's University Hospital, Imagine Institute Affiliate, Université de Paris Cité, Paris, France. Department of Paediatrics, AOU Città della Salute e della Scienza di Torino, University of Torino, Turin, Italy. Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil. Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Medical Faculty, Dusseldorf, Germany. Marmara University School of Medicine Department of Pediatric Endocrinology, Istanbul, Turkey. Royal Children's Hospital/University of Melbourne, Parkville, Australia. Department of Paediatric Cardiology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. Child Neurology Unit - C.O.A.L.A. (Center for diagnosis and treatment of leukodystrophies), V. Buzzi Children's Hospital, Milano, Italy. Private paediatric Neurology practice Dr A van der Walt, Durbanville, South Africa. University of Lille, Lille, France. Department of Paediatrics, Flevoziekenhuis, Almere, The Netherlands. Department of Internal and Pediatric Nursing, Institute of Nursing and Midwifery, Medical University of Gdańsk, Gdańsk, Poland. Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. University Children's Hospital Regensburg (KUNO), University of Regensburg, Campus St. Hedwig, Regensburg, Germany. Child Neurology Unit, Fondazione IRCCS, Istituto Neurologico Carlo Besta, Milan, Italy. Pediatric Endocrinology Unit, Kaplan Medical center, Rehovot and the Hebrew University of Jerusalem, Jerusalem, Israel. Emma Children's Hospital, Department of Paediatric Endocrinology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands. Academic Center for Thyroid Diseases, Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands. w.e.visser@erasmusmc.nl.

Abstract summary 

Predicting and quantifying phenotypic consequences of genetic variants in rare disorders is a major challenge, particularly pertinent for 'actionable' genes such as thyroid hormone transporter MCT8 (encoded by the X-linked SLC16A2 gene), where loss-of-function (LoF) variants cause a rare neurodevelopmental and (treatable) metabolic disorder in males. The combination of deep phenotyping data with functional and computational tests and with outcomes in population cohorts, enabled us to: (i) identify the genetic aetiology of divergent clinical phenotypes of MCT8 deficiency with genotype-phenotype relationships present across survival and 24 out of 32 disease features; (ii) demonstrate a mild phenocopy in ~400,000 individuals with common genetic variants in MCT8; (iii) assess therapeutic effectiveness, which did not differ among LoF-categories; (iv) advance structural insights in normal and mutated MCT8 by delineating seven critical functional domains; (v) create a pathogenicity-severity MCT8 variant classifier that accurately predicted pathogenicity (AUC:0.91) and severity (AUC:0.86) for 8151 variants. Our information-dense mapping provides a generalizable approach to advance multiple dimensions of rare genetic disorders.

Authors & Co-authors:  Groeneweg Stefan S van Geest Ferdy S FS Martín Mariano M Dias Mafalda M Frazer Jonathan J Medina-Gomez Carolina C Sterenborg Rosalie B T M RBTM Wang Hao H Dolcetta-Capuzzo Anna A de Rooij Linda J LJ Teumer Alexander A Abaci Ayhan A van den Akker Erica L T ELT Ambegaonkar Gautam P GP Armour Christine M CM Bacos Iiuliu I Bakhtiani Priyanka P Barca Diana D Bauer Andrew J AJ van den Berg Sjoerd A A SAA van den Berge Amanda A Bertini Enrico E van Beynum Ingrid M IM Brunetti-Pierri Nicola N Brunner Doris D Cappa Marco M Cappuccio Gerarda G Castellotti Barbara B Castiglioni Claudia C Chatterjee Krishna K Chesover Alexander A Christian Peter P Coenen-van der Spek Jet J de Coo Irenaeus F M IFM Coutant Regis R Craiu Dana D Crock Patricia P DeGoede Christian C Demir Korcan K Dewey Cheyenne C Dica Alice A Dimitri Paul P Dremmen Marjolein H G MHG Dubey Rachana R Enderli Anina A Fairchild Jan J Gallichan Jonathan J Garibaldi Luigi L George Belinda B Gevers Evelien F EF Greenup Erin E Hackenberg Annette A Halász Zita Z Heinrich Bianka B Hurst Anna C AC Huynh Tony T Isaza Amber R AR Klosowska Anna A van der Knoop Marieke M MM Konrad Daniel D Koolen David A DA Krude Heiko H Kulkarni Abhishek A Laemmle Alexander A LaFranchi Stephen H SH Lawson-Yuen Amy A Lebl Jan J Leeuwenburgh Selmar S Linder-Lucht Michaela M López Martí Anna A Lorea Cláudia F CF Lourenço Charles M CM Lunsing Roelineke J RJ Lyons Greta G Malikova Jana Krenek JK Mancilla Edna E EE McCormick Kenneth L KL McGowan Anne A Mericq Veronica V Lora Felipe Monti FM Moran Carla C Muller Katalin E KE Nicol Lindsey E LE Oliver-Petit Isabelle I Paone Laura L Paul Praveen G PG Polak Michel M Porta Francesco F Poswar Fabiano O FO Reinauer Christina C Rozenkova Klara K Seckold Rowen R Seven Menevse Tuba T Simm Peter P Simon Anna A Singh Yogen Y Spada Marco M Stals Milou A M MAM Stegenga Merel T MT Stoupa Athanasia A Subramanian Gopinath M GM Szeifert Lilla L Tonduti Davide D Turan Serap S Vanderniet Joel J van der Walt Adri A Wémeau Jean-Louis JL van Wermeskerken Anne-Marie AM Wierzba Jolanta J de Wit Marie-Claire Y MY Wolf Nicole I NI Wurm Michael M Zibordi Federica F Zung Amnon A Zwaveling-Soonawala Nitash N Rivadeneira Fernando F Meima Marcel E ME Marks Debora S DS Nicola Juan P JP Chen Chi-Hua CH Medici Marco M Visser W Edward WE

Study Outcome 

Source Link: Visit source

Statistics
Citations :  Rehm, H. L. et al. ClinGen-the Clinical Genome Resource. N. Engl. J. Med372, 2235–2242 (2015).
Authors :  122
Identifiers
Doi : 2479
SSN : 2041-1723
Study Population
Male,Female
Mesh Terms
Humans
Other Terms
Study Design
Study Approach
Country of Study
Publication Country
England