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

• DOI: 10.1038/s41467-025-56628-w
• Publication Date: 2025-03-12T21:37:48Z
• Authors: Stefan Groeneweg; Ferdy S. van Geest; Mariano Martín; Mafalda Dias; Jonathan Frazer; Carolina Medina-G...; Rosalie B. T. M. ...; Hao Wang; Anna Dolcetta-Cap...; Linda J. de Rooij; Alexander Teumer; Ayhan Abaci; Erica L. T. van d...; Gautam P. Ambegao...; Christine M. Armour; Iiuliu Bacos; Priyanka Bakhtiani; Diana Barca; Andrew J. Bauer; Sjoerd A. A. van ...; Amanda van den Berge; Enrico Bertini; Ingrid M. van Beynum; Nicola Brunetti-P...; Doris Brunner; Marco Cappa; Gerarda Cappuccio; Barbara Castellotti; Claudia Castiglioni; Krishna Chatterjee; Alexander Chesover; Peter Christian; Jet Coenen-van de...; Irenaeus F. M. de...; Regis Coutant; Dana Craiu; Patricia Crock; Christian DeGoede; Korcan Demir; Cheyenne Dewey; Alice Dica; Paul Dimitri; Marjolein H. G. D...; 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. van de...; Daniel Konrad; David A. Koolen; Heiko Krude; Abhishek Kulkarni; Alexander Laemmle; Stephen H. LaFranchi; Amy Lawson-Yuen; Jan Lebl; Selmar Leeuwenburgh; Michaela Linder-L...; 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-P...; 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. Subra...; Lilla Szeifert; Davide Tonduti; Serap Turan; Joel Vanderniet; Adri van der Walt; Jean-Louis Wémeau; Anne-Marie van We...; Jolanta Wierzba; Marie-Claire Y. d...; Nicole I. Wolf; Michael Wurm; Federica Zibordi; Amnon Zung; Nitash Zwaveling-...; Fernando Rivadeneira; Marcel E. Meima; Debora S. Marks; Juan P. Nicola; Chi-Hua Chen; Marco Medici; W. Edward Visser

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.