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

Stefan Groeneweg, Ferdy S. Geest, Mariano Martín, Mafalda Dias, Jonathan Frazer, Carolina Medina-Gomez, Rosalie B. T. M. Sterenborg, Hao Wang, Anna Dolcetta-Capuzzo, Linda J. Rooij, Alexander Teumer, Ayhan Abaci, Erica L. T. Akker, Gautam P. Ambegaonkar, Christine M. Armour, Iiuliu Bacos, Priyanka Bakhtiani, Diana Barca, Andrew J. Bauer, Sjoerd A. A. Berg, Amanda Berge, Enrico Bertini, Ingrid M. Beynum, Nicola Brunetti-Pierri, Doris Brunner, Marco Cappa, Gerarda Cappuccio, Barbara Castellotti, Claudia Castiglioni, Krishna Chatterjee, Alexander Chesover, Peter Christian, Jet Coenen- van der Spek, Irenaeus F. M. Coo, Regis Coutant, Dana Craiu, Patricia Crock, Christian DeGoede, Korcan Demir, Cheyenne Dewey, Alice Dica, Paul Dimitri, Marjolein H. G. Dremmen, Rachana Dubey, Anina Enderli, Jan Fairchild, Jonathan Gallichan, Luigi Garibaldi, Belinda George, Evelien F. Gevers, Erin Greenup, Annette Hackenberg, Zita Halász, Bianka Heinrich, Anna C. Hurst, Tony Huynh, Amber R. Isaza, Anna Klosowska, Marieke M. Knoop, Daniel Konrad, David A. Koolen, Heiko Krude, Abhishek Kulkarni, Alexander Laemmle, Stephen H. LaFranchi, Amy Lawson-Yuen, Jan Lebl, Selmar Leeuwenburgh, Michaela Linder-Lucht, Anna López Martí, Cláudia F. Lorea, Charles M. Lourenço, Roelineke J. Lunsing, Greta Lyons, Jana Krenek Malikova, Edna E. Mancilla, Kenneth L. McCormick, Anne McGowan, Veronica Mericq, Felipe Monti Lora, Carla Moran, Katalin E. Muller, Lindsey E. Nicol, Isabelle Oliver-Petit, Laura Paone, Praveen G. Paul, Michel Polak, Francesco Porta, Fabiano O. Poswar, Christina Reinauer, Klara Rozenkova, Rowen Seckold, Tuba Seven Menevse, Peter Simm, Anna Simon, Yogen Singh, Marco Spada, Milou A. M. Stals, Merel T. Stegenga, Athanasia Stoupa, Gopinath M. Subramanian, Lilla Szeifert, Davide Tonduti, Serap Turan, Joel Vanderniet, Adri Walt, Jean-Louis Wémeau, Anne-Marie Wermeskerken, Jolanta Wierzba, Marie-Claire Y. Wit, Nicole I. Wolf, Michael Wurm, Federica Zibordi, Amnon Zung, Nitash Zwaveling-Soonawala, Fernando Rivadeneira, Marcel E. Meima, Debora S. Marks, Juan P. Nicola, Chi-Hua Chen, Marco Medici and W. Edward Visser ()
Additional contact information
Stefan Groeneweg: Erasmus Medical Centre
Ferdy S. Geest: Erasmus Medical Centre
Mariano Martín: National University of Córdoba
Mafalda Dias: Harvard Medical School
Jonathan Frazer: Harvard Medical School
Carolina Medina-Gomez: Erasmus University Medical Center
Rosalie B. T. M. Sterenborg: Erasmus Medical Centre
Hao Wang: University of California San Diego
Anna Dolcetta-Capuzzo: Erasmus Medical Centre
Linda J. Rooij: Erasmus Medical Centre
Alexander Teumer: University Medicine Greifswald
Ayhan Abaci: Dokuz Eylul University
Erica L. T. Akker: Erasmus Medical Centre -Sophia Children’s Hospital
Gautam P. Ambegaonkar: Cambridge University Hospitals NHS Foundation Trust
Christine M. Armour: University of Ottawa
Iiuliu Bacos: Centrul Medical Dr. Bacos Cosma
Priyanka Bakhtiani: University of Louisville
Diana Barca: Paediatric Neurology Discipline II
Andrew J. Bauer: Children’s Hospital of Philadelphia
Sjoerd A. A. Berg: Erasmus Medical Center
Amanda Berge: Erasmus Medical Centre
Enrico Bertini: Bambino Gesu’ Children’s Research Hospital IRCCS
Ingrid M. Beynum: Erasmus Medical Centre - Sophia Children’s Hospital
Nicola Brunetti-Pierri: Federico II University
Doris Brunner: Gottfried Preyer’s Children Hospital
Marco Cappa: IRCCS
Gerarda Cappuccio: Federico II University
Barbara Castellotti: Fondazione IRCCS Istituto Neurologico Carlo Besta
Claudia Castiglioni: Universidad Finis Terrae
Krishna Chatterjee: University of Cambridge
Alexander Chesover: University of Toronto
Peter Christian: East Kent Hospitals University NHS Foundation Trust
Jet Coenen- van der Spek: Radboud University Medical Center (Radboudumc)
Irenaeus F. M. Coo: MHeNs School for Mental Health and Neuroscience
Regis Coutant: University Hospital
Dana Craiu: Paediatric Neurology Discipline II
Patricia Crock: University of Newcastle
Christian DeGoede: Lancashire Teaching Hospitals NHS Trust
Korcan Demir: Dokuz Eylul University
Cheyenne Dewey: MultiCare Health System
Alice Dica: Paediatric Neurology Discipline II
Paul Dimitri: Western Bank
Marjolein H. G. Dremmen: Erasmus Medical Centre – Sophia’s Children Hospital
Rachana Dubey: Medanta Superspeciality Hospital
Anina Enderli: University of Zurich
Jan Fairchild: Women’s and Children’s Hospital
Jonathan Gallichan: Plymouth Hospitals NHS Trust
Luigi Garibaldi: UPMC Children’s Hospital of Pittsburgh
Belinda George: St. John’s Medical College Hospital
Evelien F. Gevers: Queen Mary University of London
Erin Greenup: University of Alabama at Birmingham
Annette Hackenberg: University of Zurich
Zita Halász: Semmelweis University Budapest
Bianka Heinrich: University of Zurich
Anna C. Hurst: University of Alabama at Birmingham
Tony Huynh: South Brisbane
Amber R. Isaza: Children’s Hospital of Philadelphia
Anna Klosowska: Medical University of Gdańsk
Marieke M. Knoop: Erasmus Medical Centre
Daniel Konrad: University of Zurich
David A. Koolen: Radboud University Medical Center (Radboudumc)
Heiko Krude: Charité-Universitätsmedizin Berlin
Abhishek Kulkarni: SRCC Children’s Hospital
Alexander Laemmle: University Hospital Bern
Stephen H. LaFranchi: Oregon Health & Sciences University
Amy Lawson-Yuen: MultiCare Health System
Jan Lebl: University Hospital Motol
Selmar Leeuwenburgh: Erasmus Medical Centre
Michaela Linder-Lucht: University Hospital Freiburg
Anna López Martí: Erasmus Medical Centre
Cláudia F. Lorea: Teaching Hospital of Universidade Federal de Pelotas
Charles M. Lourenço: Faculdade de Medicina de São José do Rio Preto
Roelineke J. Lunsing: University of Groningen
Greta Lyons: University of Cambridge
Jana Krenek Malikova: University Hospital Motol
Edna E. Mancilla: Children’s Hospital of Philadelphia
Kenneth L. McCormick: University of Alabama at Birmingham
Anne McGowan: University of Cambridge
Veronica Mericq: Clinica Las Condes
Felipe Monti Lora: Sabara Children’s Hospital
Carla Moran: University of Cambridge
Katalin E. Muller: Heim Pal National Pediatric Institute
Lindsey E. Nicol: Oregon Health & Sciences University
Isabelle Oliver-Petit: Toulouse University Hospital
Laura Paone: IRCCS
Praveen G. Paul: Christian Medical College
Michel Polak: Université de Paris Cité
Francesco Porta: University of Torino
Fabiano O. Poswar: Hospital de Clínicas de Porto Alegre
Christina Reinauer: Medical Faculty
Klara Rozenkova: University Hospital Motol
Rowen Seckold: University of Newcastle
Tuba Seven Menevse: Marmara University School of Medicine Department of Pediatric Endocrinology
Peter Simm: Royal Children’s Hospital/University of Melbourne
Anna Simon: Christian Medical College
Yogen Singh: Cambridge University Hospitals NHS Foundation Trust
Marco Spada: University of Torino
Milou A. M. Stals: Erasmus Medical Centre
Merel T. Stegenga: Erasmus Medical Centre
Athanasia Stoupa: Université de Paris Cité
Gopinath M. Subramanian: University of Newcastle
Lilla Szeifert: Semmelweis University Budapest
Davide Tonduti: V. Buzzi Children’s Hospital
Serap Turan: Marmara University School of Medicine Department of Pediatric Endocrinology
Joel Vanderniet: University of Newcastle
Adri Walt: Private paediatric Neurology practice Dr A van der Walt
Jean-Louis Wémeau: University of Lille
Anne-Marie Wermeskerken: Flevoziekenhuis
Jolanta Wierzba: Medical University of Gdańsk
Marie-Claire Y. Wit: Erasmus Medical Centre
Nicole I. Wolf: Vrije Universiteit Amsterdam
Michael Wurm: Campus St. Hedwig
Federica Zibordi: Istituto Neurologico Carlo Besta
Amnon Zung: Rehovot and the Hebrew University of Jerusalem
Nitash Zwaveling-Soonawala: University of Amsterdam
Fernando Rivadeneira: Erasmus University Medical Center
Marcel E. Meima: Erasmus Medical Centre
Debora S. Marks: Harvard Medical School
Juan P. Nicola: National University of Córdoba
Chi-Hua Chen: University of California San Diego
Marco Medici: Erasmus Medical Centre
W. Edward Visser: Erasmus Medical Centre

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-56628-w

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