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Mapping variants in thyroid hormone transporter MCT8 to disease severity by genomic, phenotypic, functional,
Stefan Groeneweg1, Ferdy S van Geest1, Mariano Martín2,3
1Academic Center for Thyroid Diseases, Department of Internal Medicine, Erasmus Medical Centre, Rotterdam, The Netherlands.
Nature Communications
|March 13, 2025
Summary
Researchers mapped genetic variants in the MCT8 gene, revealing genotype-phenotype links for MCT8 deficiency and identifying a mild phenocopy in the general population. This work aids in understanding rare genetic disorders.
Area of Science:
- Genetics
- Molecular Biology
- Rare Diseases
Background:
- Predicting phenotypic consequences of genetic variants in rare disorders is challenging.
- The thyroid hormone transporter MCT8 (SLC16A2 gene) is actionable, with loss-of-function (LoF) variants causing a rare neurodevelopmental and metabolic disorder in males.
Purpose of the Study:
- To establish genotype-phenotype relationships for MCT8 deficiency.
- To investigate common variants in MCT8 and their phenotypic effects.
- To assess therapeutic effectiveness and advance structural insights into MCT8.
Main Methods:
- Deep phenotyping, functional assays, computational analysis, and population cohort outcomes.
- Analysis of 8151 MCT8 variants.
- Development of a pathogenicity-severity classifier.
Main Results:
- Identified genetic etiology for divergent MCT8 deficiency phenotypes, with genotype-phenotype relationships for survival and 24/32 disease features.
- Demonstrated a mild phenocopy in ~400,000 individuals with common MCT8 variants.
- Therapeutic effectiveness did not differ among LoF categories; delineated seven critical functional domains of MCT8.
- Created a variant classifier with high accuracy for pathogenicity (AUC:0.91) and severity (AUC:0.86).
Conclusions:
- The study provides an information-dense map of MCT8 variants, advancing understanding of MCT8 deficiency.
- The findings offer a generalizable approach for studying rare genetic disorders.
- Established genotype-phenotype correlations and a predictive classifier for MCT8 variants.
