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Nature communications · 2025

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

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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

Аннотация

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.

Предметные рубрики MeSH

ИП Урсолов Владлен Сергеевич

ИНН 500118482352 · ОГРНИП 314500117700049

Реквизиты и контакты