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

Journal: Nature communications
PMID: 40075072

Abstract

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

  • Stefan Groeneweg
    Academic Center for Thyroid Diseases, Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands.
  • Ferdy S van Geest
    Academic Center for Thyroid Diseases, Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands.
  • Mariano Martín
    Department of Clinical Biochemistry (CIBICI-CONICET), Faculty of Chemical Sciences, National University of Córdoba, Córdoba, Argentina.
  • Mafalda Dias
    Marks Group, Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
  • Jonathan Frazer
    Marks Group, Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
  • Carolina Medina-Gomez
    Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
  • Rosalie B T M Sterenborg
    Academic Center for Thyroid Diseases, Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands.
  • Hao Wang
    Department of Cardiology, Second Medical Center, Chinese PLA General Hospital, Beijing, China.
  • Anna Dolcetta-Capuzzo
    Academic Center for Thyroid Diseases, Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands.
  • Linda J de Rooij
    Academic Center for Thyroid Diseases, Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands.
  • Alexander Teumer
    Institute for Community Medicine, SHIP/Clinical-Epidemiological Research, University Medicine Greifswald, Greifswald, Germany.
  • Ayhan Abaci
    Division of Pediatric Endocrinology, Faculty of Medicine, Dokuz Eylul University, İzmir, Turkey.
  • Erica L T van den Akker
    Department of Paediatrics, Division of Endocrinology, Erasmus Medical Centre -Sophia Children's Hospital, Rotterdam, The Netherlands.
  • Gautam P Ambegaonkar
    Department of Paediatric Neurology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
  • Christine M Armour
    Children's Hospital of Eastern Ontario Research Institute, Ottawa, Canada.
  • Iiuliu Bacos
    Centrul Medical Dr. Bacos Cosma, Timisoara, Romania.
  • Priyanka Bakhtiani
    University of Louisville, Louisville, KY, USA.
  • Diana Barca
    Carol Davila University of Medicine, Department of Clinical Neurosciences, Paediatric Neurology Discipline II, Bucharest, Romania.
  • Andrew J Bauer
    Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • Sjoerd A A van den Berg
    Diagnostic Laboratory for Endocrinology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands.
  • Amanda van den Berge
    Academic Center for Thyroid Diseases, Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands.
  • Enrico Bertini
    Unit of Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, IRCCS Bambino Gesù Children's Hospital, Piazza S. Onofrio 4, 00165, Rome, Italy. enricosilvio.bertini@opbg.net.
  • Ingrid M van Beynum
    Department of Pediatrics, Division of Pediatric Cardiology, Erasmus Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands.
  • Nicola Brunetti-Pierri
    Department of Translational Medicine, Federico II University, 80131, Naples, Italy.
  • Doris Brunner
    Gottfried Preyer's Children Hospital, Vienna, Austria.
  • Marco Cappa
    Research Area for Innovative Therapies in Endocrinopathies, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
  • Gerarda Cappuccio
    Department of Translational Medicine, Federico II University, 80131, Naples, Italy.
  • Barbara Castellotti
    Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
  • Claudia Castiglioni
    Department of Neurology, Clinica Meds, School of Medicine, Universidad Finis Terrae, Santiago, Chile.
  • Krishna Chatterjee
    Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
  • Alexander Chesover
    Division of Endocrinology, The Hospital for Sick Children and Department of Paediatrics, University of Toronto, Toronto, M5G 1×8, Canada.
  • Peter Christian
    East Kent Hospitals University NHS Foundation Trust, Ashford, UK.
  • Jet Coenen-van der Spek
    Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
  • Irenaeus F M de Coo
    Department of Toxicogenomics, Unit Clinical Genomics, Maastricht University, MHeNs School for Mental Health and Neuroscience, Maastricht, The Netherlands.
  • Regis Coutant
    Department of Pediatric Endocrinology and Diabetology, University Hospital, Angers, France.
  • Dana Craiu
    Carol Davila University of Medicine, Department of Clinical Neurosciences, Paediatric Neurology Discipline II, Bucharest, Romania.
  • Patricia Crock
    John Hunter Children's Hospital, Hunter Medical Research Institute, University of Newcastle, New Lambton Heights, Australia.
  • Christian DeGoede
    Department of Paediatric Neurology, Clinical Research Facility, Lancashire Teaching Hospitals NHS Trust, Lancashire, UK.
  • Korcan Demir
  • Cheyenne Dewey
    Genomics Institute Mary Bridge Children's Hospital, MultiCare Health System, Tacoma, WA, USA.
  • Alice Dica
    Carol Davila University of Medicine, Department of Clinical Neurosciences, Paediatric Neurology Discipline II, Bucharest, Romania.
  • Paul Dimitri
    NIHR Children and Young People MedTech Cooperative, Sheffield Children's Hospital NHS Foundation Trust, Sheffield, UK.
  • Marjolein H G Dremmen
    Division of Paediatric Radiology, Erasmus Medical Centre - Sophia's Children Hospital, Rotterdam, The Netherlands.
  • Rachana Dubey
    Medanta Superspeciality Hospital, Indore, India.
  • Anina Enderli
    Department of Neuropediatrics, University Children's Hospital, University of Zurich, Zurich, Switzerland.
  • Jan Fairchild
    Department of Diabetes and Endocrinology, Women's and Children's Hospital, North Adelaide, 5066, South Australia, Australia.
  • Jonathan Gallichan
    Plymouth Hospitals NHS Trust, Plymouth, UK.
  • Luigi Garibaldi
    UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
  • Belinda George
    Department of Endocrinology, St. John's Medical College Hospital, Bengaluru, India.
  • Evelien F Gevers
    Centre for Endocrinology, William Harvey Research institute, Queen Mary University of London, London, UK.
  • Erin Greenup
    Department of Pediatrics, Division of Pediatric Endocrinology, University of Alabama at Birmingham, Birmingham, AL, USA.
  • Annette Hackenberg
    Department of Neuropediatrics, University Children's Hospital, University of Zurich, Zurich, Switzerland.
  • Zita Halász
    Pediatric Center, Semmelweis University Budapest, Budapest, Hungary.
  • Bianka Heinrich
    Department of Neuropediatrics, University Children's Hospital, University of Zurich, Zurich, Switzerland.
  • Anna C Hurst
    Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA.
  • Tony Huynh
    Department of Endocrinology & Diabetes, Queensland Children's Hospital, South Brisbane, Queensland, Australia.
  • Amber R Isaza
    Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • Anna Klosowska
    Department of Pediatrics, Hematology and Oncology, Medical University of Gdańsk, Gdańsk, Poland.
  • Marieke M van der Knoop
    Department of Paediatric Neurology, Erasmus Medical Centre, Rotterdam, The Netherlands.
  • Daniel Konrad
    Division of Pediatric Endocrinology and Diabetology and Children's Research Center, University Children's Hospital, University of Zurich, Zurich, Switzerland.
  • David A Koolen
    Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
  • Heiko Krude
    Institute of Experimental Paediatric Endocrinology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
  • Abhishek Kulkarni
    Department of Paediatric Endocrinology, SRCC Children's Hospital, Mumbai, India.
  • Alexander Laemmle
    Institute of Clinical Chemistry and Department of Pediatrics, Inselspital, University Hospital Bern, Bern, Switzerland.
  • Stephen H LaFranchi
    Department of Pediatrics, Doernbecher Children's Hospital, Oregon Health & Sciences University, Portland, OR, USA.
  • Amy Lawson-Yuen
    Genomics Institute Mary Bridge Children's Hospital, MultiCare Health System, Tacoma, WA, USA.
  • Jan Lebl
    Department of Paediatrics, Second Faculty of Medicine, Charles University, University Hospital Motol, Prague, Czech Republic.
  • Selmar Leeuwenburgh
    Academic Center for Thyroid Diseases, Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands.
  • Michaela Linder-Lucht
    Division of Neuropediatrics and Muscular Disorders, Department of Pediatrics and Adolescent Medicine, University Hospital Freiburg, Freiburg, Germany.
  • Anna López Martí
    Academic Center for Thyroid Diseases, Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands.
  • Cláudia F Lorea
    Teaching Hospital of Universidade Federal de Pelotas, Pelotas, Brazil.
  • Charles M Lourenço
    National Reference Center for Rare Diseases, Faculdade de Medicina de São José do Rio Preto, São José do Rio Preto, Brazil.
  • Roelineke J Lunsing
    Department of Child Neurology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
  • Greta Lyons
    Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
  • Jana Krenek Malikova
    Department of Paediatrics, Second Faculty of Medicine, Charles University, University Hospital Motol, Prague, Czech Republic.
  • Edna E Mancilla
    Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • Kenneth L McCormick
    Department of Pediatrics, Division of Pediatric Endocrinology, University of Alabama at Birmingham, Birmingham, AL, USA.
  • Anne McGowan
    Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
  • Veronica Mericq
    Division of Endocrinology, University of Santiago, Santiago, Chile.
  • Felipe Monti Lora
    Pediatric Endocrinology Group, Sabara Children's Hospital, São Paulo, Brazil.
  • Carla Moran
    Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
  • Katalin E Muller
    Heim Pal National Pediatric Institute, Budapest, Hungary.
  • Lindsey E Nicol
    Department of Pediatrics, Doernbecher Children's Hospital, Oregon Health & Sciences University, Portland, OR, USA.
  • Isabelle Oliver-Petit
    Department of Paediatric Endocrinology and Genetics, Children's Hospital, Toulouse University Hospital, Toulouse, France.
  • Laura Paone
    Endocrinology and Diabetology Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
  • Praveen G Paul
    Department of Paediatrics, Christian Medical College, Vellore, India.
  • Michel Polak
    Paediatric Endocrinology, Diabetology and Gynaecology, Department, Necker Children's University Hospital, Imagine Institute Affiliate, Université de Paris Cité, Paris, France.
  • Francesco Porta
    Department of Paediatrics, AOU Città della Salute e della Scienza di Torino, University of Torino, Turin, Italy.
  • Fabiano O Poswar
    Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
  • Christina Reinauer
    Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Medical Faculty, Dusseldorf, Germany.
  • Klara Rozenkova
    Department of Paediatrics, Second Faculty of Medicine, Charles University, University Hospital Motol, Prague, Czech Republic.
  • Rowen Seckold
    John Hunter Children's Hospital, Hunter Medical Research Institute, University of Newcastle, New Lambton Heights, Australia.
  • Tuba Seven Menevse
    Marmara University School of Medicine Department of Pediatric Endocrinology, Istanbul, Turkey.
  • Peter Simm
    Royal Children's Hospital/University of Melbourne, Parkville, Australia.
  • Anna Simon
    Department of Paediatrics, Christian Medical College, Vellore, India.
  • Yogen Singh
    Department of Paediatric Cardiology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
  • Marco Spada
    Department of Paediatrics, AOU Città della Salute e della Scienza di Torino, University of Torino, Turin, Italy.
  • Milou A M Stals
    Academic Center for Thyroid Diseases, Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands.
  • Merel T Stegenga
    Academic Center for Thyroid Diseases, Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands.
  • Athanasia Stoupa
    Paediatric Endocrinology, Diabetology and Gynaecology, Department, Necker Children's University Hospital, Imagine Institute Affiliate, Université de Paris Cité, Paris, France.
  • Gopinath M Subramanian
    John Hunter Children's Hospital, Hunter Medical Research Institute, University of Newcastle, New Lambton Heights, Australia.
  • Lilla Szeifert
    Pediatric Center, Semmelweis University Budapest, Budapest, Hungary.
  • Davide Tonduti
    Child Neurology Unit - C.O.A.L.A. (Center for diagnosis and treatment of leukodystrophies), V. Buzzi Children's Hospital, Milano, Italy.
  • Serap Turan
    Marmara University School of Medicine Department of Pediatric Endocrinology, Istanbul, Turkey.
  • Joel Vanderniet
    John Hunter Children's Hospital, Hunter Medical Research Institute, University of Newcastle, New Lambton Heights, Australia.
  • Adri van der Walt
    Private paediatric Neurology practice Dr A van der Walt, Durbanville, South Africa.
  • Jean-Louis Wémeau
    University of Lille, Lille, France.
  • Anne-Marie van Wermeskerken
    Department of Paediatrics, Flevoziekenhuis, Almere, The Netherlands.
  • Jolanta Wierzba
    Department of Internal and Pediatric Nursing, Institute of Nursing and Midwifery, Medical University of Gdańsk, Gdańsk, Poland.
  • Marie-Claire Y de Wit
    Department of Paediatric Neurology, Erasmus Medical Centre, Rotterdam, The Netherlands.
  • Nicole I Wolf
    Department of Child Neurology, Amsterdam Leukodystrophy Center, Emma Children's Hospital, Amsterdam University Medical Centers, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
  • Michael Wurm
    University Children's Hospital Regensburg (KUNO), University of Regensburg, Campus St. Hedwig, Regensburg, Germany.
  • Federica Zibordi
    Child Neurology Unit, Fondazione IRCCS, Istituto Neurologico Carlo Besta, Milan, Italy.
  • Amnon Zung
    Pediatric Endocrinology Unit, Kaplan Medical center, Rehovot and the Hebrew University of Jerusalem, Jerusalem, Israel.
  • Nitash Zwaveling-Soonawala
    Department of Paediatric Endocrinology, Emma Children's Hospital, Amsterdam Gastroenterology, Endocrinology & Metabolism, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.
  • Fernando Rivadeneira
    Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, Netherlands.
  • Marcel E Meima
    Academic Center for Thyroid Diseases, Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands.
  • Debora S Marks
    Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA. Electronic address: debbie@hms.harvard.edu.
  • Juan P Nicola
    Department of Clinical Biochemistry (CIBICI-CONICET), Faculty of Chemical Sciences, National University of Córdoba, Córdoba, Argentina.
  • Chi-Hua Chen
    Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA, USA.
  • Marco Medici
    Academic Center for Thyroid Diseases, Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands.
  • W Edward Visser
    Academic Center for Thyroid Diseases, Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands. w.e.visser@erasmusmc.nl.

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