Mapping variants in thyroid hormone transporter MCT8 to disease severity by genomic, phenotypic, functional, structural and deep learning integration
| Title: | Mapping variants in thyroid hormone transporter MCT8 to disease severity by genomic, phenotypic, functional, structural and deep learning integration |
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| Authors: | 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 |
| Source: | Groeneweg, S, van Geest, F S, Martín, M, Dias, M, Frazer, J, Medina-Gomez, C, Sterenborg, R B T M, Wang, H, Dolcetta-Capuzzo, A, de Rooij, L J, Teumer, A, Abaci, A, van den Akker, E L T, Ambegaonkar, G P, Armour, C M, Bacos, I, Bakhtiani, P, Barca, D, Bauer, A J, van den Berg, S A A, van den Berge, A, Bertini, E, van Beynum, I M, Brunetti-Pierri, N, Brunner, D, Cappa, M, Cappuccio, G, Castellotti, B, Castiglioni, C, Chatterjee, K, Chesover, A, Christian, P, Coenen-van der Spek, J, de Coo, I F M, Coutant, R, Craiu, D, .... |
| Publication Year: | 2025 |
| Description: | 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. |
| Document Type: | article in journal/newspaper |
| File Description: | application/pdf |
| Language: | English |
| ISSN: | 2041-1723 |
| Relation: | info:eu-repo/semantics/altIdentifier/pmid/40075072; info:eu-repo/semantics/altIdentifier/pissn/2041-1723; info:eu-repo/semantics/altIdentifier/eissn/2041-1723 |
| DOI: | 10.1038/s41467-025-56628-w |
| Availability: | https://pure.eur.nl/en/publications/a261c0ce-f8a1-4b14-940b-5953f4b33300; https://doi.org/10.1038/s41467-025-56628-w; https://pure.eur.nl/ws/files/188983594/s41467-025-56628-w.pdf; https://www.scopus.com/pages/publications/105000111424 |
| Rights: | info:eu-repo/semantics/openAccess ; http://creativecommons.org/licenses/by/4.0/ |
| Accession Number: | edsbas.6F0491E5 |
| Database: | BASE |