Mapping variants in thyroid hormone transporter MCT8 to disease severity by genomic, phenotypic, functional, structural and deep learning integration
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.
Article Details
Authors (122)
Stefan Groeneweg
Ferdy S. van Geest
Mariano Martín
Institute for Bioengineering of Catalonia, The Barcelona Institute of Science and Technology
Mafalda Dias
Jonathan Frazer
Carolina Medina-Gomez
Rosalie B. T. M. Sterenborg
Hao Wang
Division of Quantitative Sciences, Department of Oncology Johns Hopkins University School of Medicine Baltimore Maryland USA
Anna Dolcetta-Capuzzo
Linda J. de Rooij
Alexander Teumer
Ayhan Abaci
Erica L. T. van den Akker
Gautam P. Ambegaonkar
Christine M. Armour
Iiuliu Bacos
Priyanka Bakhtiani
Diana Barca
Andrew J. Bauer
Sjoerd A. A. van den Berg
Amanda van den Berge
Enrico Bertini
Research Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesù Children’s Research Hospital IRCCS, Rome
Ingrid M. van Beynum
Nicola Brunetti-Pierri
Doris Brunner
Marco Cappa
Physics Department, Sapienza University of Rome, P.le A. Moro 5, 00185 Rome, Italy
Gerarda Cappuccio
Barbara Castellotti
Claudia Castiglioni
Krishna Chatterjee
Alexander Chesover
Peter Christian
Jet Coenen-van der Spek
Irenaeus F. M. de 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
Queensland Children’s Hospital, South Brisbane, Australia
Amber R. Isaza
Anna Klosowska
Marieke M. van der 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
Wolfson Institute for Biomedical Research, University College London
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 van der Walt
Jean-Louis Wémeau
Anne-Marie van Wermeskerken
Jolanta Wierzba
Marie-Claire Y. de 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
W. Edward Visser