@article{
 title = {Mapping variants in thyroid hormone transporter MCT8 to disease severity by genomic, phenotypic, functional, structural and deep learning integration},
 type = {article},
 year = {2025},
 pages = {2479},
 volume = {16},
 month = {3},
 day = {12},
 id = {a9280376-14f7-3445-b637-048827edabe6},
 created = {2025-04-08T08:59:26.850Z},
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 profile_id = {a1b2ded6-b257-3e56-ac7c-9d438762d170},
 last_modified = {2025-04-08T08:59:53.073Z},
 read = {false},
 starred = {false},
 authored = {true},
 confirmed = {false},
 hidden = {false},
 private_publication = {false},
 abstract = {<p> 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 <italic>SLC16A2</italic> 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. </p>},
 bibtype = {article},
 author = {Groeneweg, Stefan and van Geest, Ferdy S. and Martín, Mariano and Dias, Mafalda and Frazer, Jonathan and Medina-Gomez, Carolina and Sterenborg, Rosalie B. T. M. and Wang, Hao and Dolcetta-Capuzzo, Anna and de Rooij, Linda J. and Teumer, Alexander and Abaci, Ayhan and van den Akker, Erica L. T. and Ambegaonkar, Gautam P. and Armour, Christine M. and Bacos, Iiuliu and Bakhtiani, Priyanka and Barca, Diana and Bauer, Andrew J. and van den Berg, Sjoerd A. A. and van den Berge, Amanda and Bertini, Enrico and van Beynum, Ingrid M. and Brunetti-Pierri, Nicola and Brunner, Doris and Cappa, Marco and Cappuccio, Gerarda and Castellotti, Barbara and Castiglioni, Claudia and Chatterjee, Krishna and Chesover, Alexander and Christian, Peter and Coenen-van der Spek, Jet and de Coo, Irenaeus F. M. and Coutant, Regis and Craiu, Dana and Crock, Patricia and DeGoede, Christian and Demir, Korcan and Dewey, Cheyenne and Dica, Alice and Dimitri, Paul and Dremmen, Marjolein H. G. and Dubey, Rachana and Enderli, Anina and Fairchild, Jan and Gallichan, Jonathan and Garibaldi, Luigi and George, Belinda and Gevers, Evelien F. and Greenup, Erin and Hackenberg, Annette and Halász, Zita and Heinrich, Bianka and Hurst, Anna C. and Huynh, Tony and Isaza, Amber R. and Klosowska, Anna and van der Knoop, Marieke M. and Konrad, Daniel and Koolen, David A. and Krude, Heiko and Kulkarni, Abhishek and Laemmle, Alexander and LaFranchi, Stephen H. and Lawson-Yuen, Amy and Lebl, Jan and Leeuwenburgh, Selmar and Linder-Lucht, Michaela and López Martí, Anna and Lorea, Cláudia F. and Lourenço, Charles M. and Lunsing, Roelineke J. and Lyons, Greta and Malikova, Jana Krenek and Mancilla, Edna E. and McCormick, Kenneth L. and McGowan, Anne and Mericq, Veronica and Lora, Felipe Monti and Moran, Carla and Muller, Katalin E. and Nicol, Lindsey E. and Oliver-Petit, Isabelle and Paone, Laura and Paul, Praveen G. and Polak, Michel and Porta, Francesco and Poswar, Fabiano O. and Reinauer, Christina and Rozenkova, Klara and Seckold, Rowen and Seven Menevse, Tuba and Simm, Peter and Simon, Anna and Singh, Yogen and Spada, Marco and Stals, Milou A. M. and Stegenga, Merel T. and Stoupa, Athanasia and Subramanian, Gopinath M. and Szeifert, Lilla and Tonduti, Davide and Turan, Serap and Vanderniet, Joel and van der Walt, Adri and Wémeau, Jean-Louis and van Wermeskerken, Anne-Marie and Wierzba, Jolanta and de Wit, Marie-Claire Y. and Wolf, Nicole I. and Wurm, Michael and Zibordi, Federica and Zung, Amnon and Zwaveling-Soonawala, Nitash and Rivadeneira, Fernando and Meima, Marcel E. and Marks, Debora S. and Nicola, Juan P. and Chen, Chi-Hua and Medici, Marco and Visser, W. Edward},
 doi = {10.1038/s41467-025-56628-w},
 journal = {Nature Communications},
 number = {1}
}

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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. </p>","bibtype":"article","author":"Groeneweg, Stefan and van Geest, Ferdy S. and Martín, Mariano and Dias, Mafalda and Frazer, Jonathan and Medina-Gomez, Carolina and Sterenborg, Rosalie B. T. M. and Wang, Hao and Dolcetta-Capuzzo, Anna and de Rooij, Linda J. and Teumer, Alexander and Abaci, Ayhan and van den Akker, Erica L. T. and Ambegaonkar, Gautam P. and Armour, Christine M. and Bacos, Iiuliu and Bakhtiani, Priyanka and Barca, Diana and Bauer, Andrew J. and van den Berg, Sjoerd A. A. and van den Berge, Amanda and Bertini, Enrico and van Beynum, Ingrid M. and Brunetti-Pierri, Nicola and Brunner, Doris and Cappa, Marco and Cappuccio, Gerarda and Castellotti, Barbara and Castiglioni, Claudia and Chatterjee, Krishna and Chesover, Alexander and Christian, Peter and Coenen-van der Spek, Jet and de Coo, Irenaeus F. 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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. 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