MCT8 deficiency is caused by LoF mutations in thyroid hormone (TH) transporter MCT8. Patients have developmental delay and abnormal thyroid function tests. The large phenotypic variability is not understood. Phenotypes arising from mutations could be employed to enhance understanding of physiology in the general population. Computational disease variant classifiers have poor predictive power to ascertain impact of MCT8 variants. We conducted a generalizable approach that addresses all abovementioned challenges.

We integrated genetic, clinical and biochemical data from 371 patients with MCT8 deficiency, accrued through combination of data from our well-phenotyped global cohort and meta-analysis of all reported cases. We evaluated impact of 108 patient mutations and 304 MCT8 variants in a full alanine-scanning by TH transport assays and linked this to phenotypic outcomes. We assessed the impact of common genetic variation in MCT8 on TFTs in ~70k individuals. Utilizing these data, an MCT8 deficiency-specific variant classifier was constructed using artificial intelligence methods.

We observed a clear genotype-phenotype relationship across a range of disease features. Functional impact of variants strongly associated with survival of patients, and developmental (e.g. motor function), clinical (e.g. seizures) and biochemical (e.g. fT4) features. Beneficial effects of the TH analogue Triac on several disease outcomes were independent of LoF category.

Our MCT8-specific classifier largely outperformed  commonly used prediction tools. Common genetic variation in MCT8 was associated with lower serum fT4, similar to patients.

The combination of deep phenotyping data from patients with MCT8 deficiency with a battery of functional and computational tests and with outcomes in population cohorts, enabled us to: (i) understand the divergent clinical phenotypes of MCT8 deficiency, (ii) assess therapy effectiveness, (iii) advance structural insights of MCT8, (iv) create a high-quality disease variant classifier, together also leveraging the role of MCT8 in non-affected individuals.