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

IF 3.3 Q2 GENETICS & HEREDITY
Kirsty McWalter, Houda Zghal Eloumi, Richard Sidlow, Ben Willis, Andrew J Bauer
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Abstract

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 (VUS). Six hundred and eleven 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 VUS. 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 patient and caregiver support.

MCT8缺乏症SLC16A2变异个体的表型谱。
单羧酸转运蛋白8 (MCT8)缺乏症是一种罕见的x连锁疾病,由SLC16A2基因的致病性变异引起,导致甲状腺激素在全身的转运功能失调。人类表型本体(HPO)术语提供了人类疾病症状学的标准化临床词汇。在这里,我们提供了一个具有完全分类的SLC16A2变体和相关HPO术语的MCT8缺陷表型谱的个体队列。我们查询了主要通过外显子组测序确定的SLC16A2变异的去鉴定遗传数据。对病历进行临床抽象,生成HPO术语。在122例SLC16A2变异个体中,我们确定了68例可能具有致病性/致病性(L/PATH)变异,54例具有不确定意义变异(VUS)。从108个SLC16A2变异个体中检索到611个不同的HPO项。常见的HPO术语包括全体性发育迟缓(79/108,73.1%)、广泛性张力低下(40/108,37.0%)和言语和语言发育迟缓(29/108,26.9%)。一些与严重MCT8缺陷表型相关的HPO术语,如发育不良、喂养困难和髓鞘形成延迟,在L/PATH变异个体中比在VUS中更常见。与甲状腺功能和/或激素水平相关的HPO术语不常被报道,甲状腺功能减退是最常报道的术语,在6个人中见过。本研究强调综合基因检测和标准化临床词汇在诊断罕见遗传条件的效用。在MCT8缺乏症中,这种方法可以帮助表征基因型-表型相关性,加快同步甲状腺激素检测,并改善患者和护理人员的支持。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
HGG Advances
HGG Advances Biochemistry, Genetics and Molecular Biology-Molecular Medicine
CiteScore
4.30
自引率
4.50%
发文量
69
审稿时长
14 weeks
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