McWalter Kirsty, Elloumi Houda Zghal, Sidlow Richard, Willis Ben, Bauer Andrew J
GeneDx LLC, Gaithersburg, MD, USA.
GeneDx LLC, Gaithersburg, MD, USA.
HGG Adv. 2025 May 13;6(3):100455. doi: 10.1016/j.xhgg.2025.100455.
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.
单羧酸转运体8（MCT8）缺乏症是一种罕见的X连锁疾病，由SLC16A2基因的致病变异引起，导致甲状腺激素在全身的转运功能失调。人类表型本体论（HPO）术语提供了人类疾病症状学的标准化临床词汇。在此，我们为MCT8缺乏症的表型谱贡献了一组具有完全分类的SLC16A2变体和相关HPO术语的个体。我们查询了主要通过外显子组测序确定的SLC16A2变体的去识别遗传数据。对病历进行临床摘要以生成HPO术语。在一组122名携带SLC16A2变体的个体中，我们鉴定出68例可能致病/致病（L/PATH）变体的病例和54例意义未明变体（VUS）的个体。对于108名具有特征性SLC16A2变体的个体，共检索到611个不同的HPO术语。常见HPO术语包括全球发育迟缓（79/108，73.1%）、全身性肌张力减退（40/108，37.0%）以及言语和语言发育迟缓（29/108，26.9%）。一些与严重MCT8缺乏症表型相关的HPO术语，如生长发育不良、喂养困难和髓鞘形成延迟，在L/PATH变体个体中比在VUS个体中更常见。与甲状腺功能和/或激素水平相关的HPO术语报告不常见，甲状腺功能减退是最常报告的术语，见于6名个体。本研究强调了全面基因检测和标准化临床词汇在诊断罕见遗传病中的实用性。在MCT8缺乏症中，这种方法有助于表征基因型-表型相关性、加快同时进行的甲状腺激素检测，并改善对受影响个体和护理人员的支持。
