Compound heterozygous GLI3 variants in siblings with thyroid hemiagenesis.
Compound heterozygous GLI3 variants in siblings with thyroid hemiagenesis.
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兄弟姐妹甲状腺功能不全患者的复合杂合GLI3变异。
DOI：
10.1007/s12020-020-02422-1
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发表时间：
2021-03
期刊：
影响因子：
3.7
通讯作者：
Ruchała M
中科院分区：
文献类型：
--
作者：
Szczepanek-Parulska E;Budny B;Borowczyk M;Zawadzka K;Sztromwasser P;Ruchała M
甲状腺偏侧成熟症(THA)是一种先天性的单侧甲状腺叶缺失，病因不明，影响0.05-0.5%的人群。这项研究的目的是确定导致两个THA兄弟姐妹甲状腺发育不良的遗传因素。我们评估了一个三代人的家庭，有两个姐妹表现出这种疾病。先证者(患者II：3)在45岁时被诊断为颈部不对称。左叶发育不全和无毒性的多结节甲状腺肿被描述。先证者的姐姐(患者II：6)甲状腺功能正常，因颈部不适在39岁时出现，左侧THA被证实。对受影响的个体进行全外显子组测序(WES)(Illumina，TruSeq Exome Kit)，并对所有已识别的变异体进行致病性评估。使用Sanger测序来确认WES数据并检查一级亲属之间的分离。在这两个兄弟姐妹中，在GLI3基因上发现了一个复合杂合性突变NM_000168.6：C.[2179G>；A]；[4039C>；A](NP_000159.3：p.[Gly727Arg]；[Gln1347Lys])，分别影响外显子14和15。根据美国医学遗传学学会的说法，变异被归类为不确定的重要性，并被发现非常罕见(GonomAD MAF 0.007131和0.00003187)。分离图谱和亲缘关系分析表明了复合杂合性的原因。我们首次发现GLI3基因的表型与GLI3基因的复合杂合突变p.[Gly727Arg]；[Gln1347Lys]在两个兄弟姐妹中存在独特的关联。
Thyroid hemiagenesis (THA) is an inborn absence of one thyroid lobe of largely unknown etiopathogenesis, affecting 0.05–0.5% population. The aim of the study was an identification of genetic factors responsible for thyroid maldevelopment in two siblings with THA. We evaluated a three-generation THA family with two sisters presenting the disorder. Proband (Patient II:3) was diagnosed at the age of 45 due to neck asymmetry. Left lobe agenesis and nontoxic multinodular goiter were depicted. Proband’s sister (Patient II:6) was euthyroid, showed up at the age of 39 due to neck discomfort and left-sided THA was demonstrated. Affected individuals were subjected to whole-exome sequencing (WES) (Illumina, TruSeq Exome Kit) and all identified variants were evaluated for pathogenicity. Sanger sequencing was used to confirm WES data and check segregation among first-degree relatives. In both siblings, a compound heterozygous mutations NM_000168.6: c.[2179G>A];[4039C>A] (NP_000159.3: p.[Gly727Arg];[Gln1347Lys]) were identified in the GLI3 gene, affecting exon 14 and 15, respectively. According to the American College of Medical Genetics, variants are classified as of uncertain significance, and were found to be very rare (GnomAD MAF 0.007131 and 0.00003187). The segregation mapping and analysis of relatives indicated causativeness of compound heterozygosity. We demonstrated for the first time a unique association of THA phenotype and the presence of compound heterozygous mutations p.[Gly727Arg];[Gln1347Lys] of GLI3 gene in two siblings.
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通讯作者：
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