The phenotypic spectrum of individuals with SLC16A2 variants in MCT8 deficiency.

Monocarboxylate transporter 8 (MCT8) deficiency is a rare, X-linked condition caused by pathogenic variants in the SLC16A2 gene, resulting in dysfunctional thyroid hormone transport throughout the body. Human Phenotype Ontology (HPO) terms provide a standardized clinical vocabulary of symptomology in human disease. Here, we contribute a cohort of individuals with fully categorized SLC16A2 variants and associated HPO terms to the phenotypic spectrum of MCT8 deficiency. We queried de-identified genetic data for SLC16A2 variants mostly determined through exome sequencing. Clinical abstraction of medical records was performed to generate HPO terms. In a cohort of 122 individuals with SLC16A2 variants, we identified 68 cases with likely pathogenic/pathogenic (L/PATH) variants and 54 individuals with variants of uncertain significance (VUSs). A total of 611 different HPO terms were retrieved for 108 individuals with characterized SLC16A2 variants. Common HPO terms included global developmental delay (79/108, 73.1%), generalized hypotonia (40/108, 37.0%), and delayed speech and language development (29/108, 26.9%). Some HPO terms associated with a severe MCT8 deficiency phenotype, such as failure to thrive, feeding difficulties, and delayed myelination, were more common in individuals with L/PATH variants than in those with VUSs. HPO terms related to thyroid function and/or hormone levels were not commonly reported, with hypothyroidism the most frequently reported term, seen in six individuals. This study highlights the utility of comprehensive genetic testing and standardized clinical vocabulary in diagnosing rare genetic conditions. In MCT8 deficiency, this approach can help characterize genotype-phenotype correlations, expedite concurrent thyroid hormone testing, and improve affected individual and caregiver support.