Mapping variants in thyroid hormone transporter MCT8 to disease severity by genomic, phenotypic, functional, structural and deep learning integration
Articolo
Data di Pubblicazione:
2025
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.
Tipologia CRIS:
03A-Articolo su Rivista
Elenco autori:
Groeneweg, Stefan; van Geest, Ferdy S.; Martín, Mariano; Dias, Mafalda; Frazer, Jonathan; Medina-Gomez, Carolina; Sterenborg, Rosalie B. T. M.; Wang, Hao; Dolcetta-Capuzzo, Anna; de Rooij, Linda J.; Teumer, Alexander; Abaci, Ayhan; van den Akker, Erica L. T.; Ambegaonkar, Gautam P.; Armour, Christine M.; Bacos, Iiuliu; Bakhtiani, Priyanka; Barca, Diana; Bauer, Andrew J.; van den Berg, Sjoerd A. A.; van den Berge, Amanda; Bertini, Enrico; van Beynum, Ingrid M.; Brunetti-Pierri, Nicola; Brunner, Doris; Cappa, Marco; Cappuccio, Gerarda; Castellotti, Barbara; Castiglioni, Claudia; Chatterjee, Krishna; Chesover, Alexander; Christian, Peter; Coenen-van der Spek, Jet; de Coo, Irenaeus F. M.; Coutant, Regis; Craiu, Dana; Crock, Patricia; DeGoede, Christian; Demir, Korcan; Dewey, Cheyenne; Dica, Alice; Dimitri, Paul; Dremmen, Marjolein H. G.; Dubey, Rachana; Enderli, Anina; Fairchild, Jan; Gallichan, Jonathan; Garibaldi, Luigi; George, Belinda; Gevers, Evelien F.; Greenup, Erin; Hackenberg, Annette; Halász, Zita; Heinrich, Bianka; Hurst, Anna C.; Huynh, Tony; Isaza, Amber R.; Klosowska, Anna; van der Knoop, Marieke M.; Konrad, Daniel; Koolen, David A.; Krude, Heiko; Kulkarni, Abhishek; Laemmle, Alexander; LaFranchi, Stephen H.; Lawson-Yuen, Amy; Lebl, Jan; Leeuwenburgh, Selmar; Linder-Lucht, Michaela; López Martí, Anna; Lorea, Cláudia F.; Lourenço, Charles M.; Lunsing, Roelineke J.; Lyons, Greta; Malikova, Jana Krenek; Mancilla, Edna E.; McCormick, Kenneth L.; McGowan, Anne; Mericq, Veronica; Lora, Felipe Monti; Moran, Carla; Muller, Katalin E.; Nicol, Lindsey E.; Oliver-Petit, Isabelle; Paone, Laura; Paul, Praveen G.; Polak, Michel; Porta, Francesco; Poswar, Fabiano O.; Reinauer, Christina; Rozenkova, Klara; Seckold, Rowen; Seven Menevse, Tuba; Simm, Peter; Simon, Anna; Singh, Yogen; Spada, Marco; Stals, Milou A. M.; Stegenga, Merel T.; Stoupa, Athanasia; Subramanian, Gopinath M.; Szeifert, Lilla; Tonduti, Davide; Turan, Serap; Vanderniet, Joel; van der Walt, Adri; Wémeau, Jean-Louis; van Wermeskerken, Anne-Marie; Wierzba, Jolanta; de Wit, Marie-Claire Y.; Wolf, Nicole I.; Wurm, Michael; Zibordi, Federica; Zung, Amnon; Zwaveling-Soonawala, Nitash; Rivadeneira, Fernando; Meima, Marcel E.; Marks, Debora S.; Nicola, Juan P.; Chen, Chi-Hua; Medici, Marco; Visser, W. Edward
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