biostudies-literatureGroeneweg SNIMH NIH HHSWellcome TrustEC | Eurostars2479https://www.ebi.ac.uk/biostudies/studies/S-EPMC11904026biostudies-literatureUnknown16(1)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 effecNature communicationsMapping variants in thyroid hormone transporter MCT8 to disease severity by genomic, phenotypic, functional, structural and deep learning integration.PMC11904026210755/Z/18/ZE113377R01 MH118281van Wermeskerken AMSeven Menevse TStals MAMKlosowska AStegenga MTGallichan JTonduti Dvan den Berg SAAGevers EFvan der Walt Ade Rooij LJvan den Akker ELTStoupa AMartin MGroeneweg SKoolen DAMoran CHuynh TBarca DLyons GMcGowan ATuran SPoswar FOKonrad DRozenkova KArmour CMHalasz ZGeorge BLunsing RJVisser WECrock PZung ACoutant Rvan Geest FSCraiu DMarks DSDubey RDolcetta-Capuzzo Ade Coo IFMHackenberg ALebl Jvan den Berge ALorea CFPaone LNicola JPWemeau JLRivadeneira FLourenco CMSimon AAbaci ALeeuwenburgh SAmbegaonkar GPTeumer ABacos IMeima MEMedina-Gomez CBrunner DSingh Yde Wit MYChatterjee KLawson-Yuen AWierzba JDeGoede CMalikova JKReinauer CWang HSeckold RCoenen-van der Spek JChristian PKulkarni AMericq VLora FMSpada MVanderniet JBertini ELinder-Lucht MKrude HChen CHFairchild JMancilla EEDemir KCastiglioni CPaul PGCappa MFrazer JOliver-Petit IWurm MLaemmle AChesover AMuller KESubramanian GMSterenborg RBTMBakhtiani PCappuccio GZwaveling-Soonawala NGreenup EDica ASimm PSzeifert LIsaza ARPorta FWolf NICastellotti BHurst ACBrunetti-Pierri NZibordi FDimitri PHeinrich BLopez Marti AMcCormick KLDewey CBauer AJEnderli AGaribaldi Lvan der Knoop MMLaFranchi SHNicol LEPolak MDias MMedici Mvan Beynum IMDremmen MHGfalseMapping variants in thyroid hormone transporter MCT8 to disease severity by genomic, phenotypic, functional, structural and deep learning integration.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 effec2025-01-01T00:00:00Z2025 Mar2026-06-02T17:27:17.658Z2025-04-05T22:11:35.373ZS-EPMC119040264007507210.1038/s41467-025-56628-w