Abstract：
OBJECTIVE: Congenital hypothyroidism (CH) is the most common endocrine disorder of the newborn; it is seen in every 3000-4000 births. Genetic features can guide treatment for patients with in situ glands. The present study aimed to contribute to the literature on CH variants and to show the benefit that genetic analysis can provide to patients in follow-up.
METHODS: A total of 52 patients (47 families) diagnosed with CH were included in the study. Overall, 32 target genes involved in thyroid physiology were investigated by next-generation sequencing (NGS).
RESULTS: In total, 29 (55 %) of the patients were male, and the rate of dysgenesis was 19.2 %. In this study, 29 of 52 patients had at least one variant in one gene involved in CH (n = 29, 33 different variants) (Including likely benign variants and variants of unknown significance). There were 21 patients (40.3 %) with gland in situ. The most common variant was DUOX2 (20 %). The second most common variants were those in the TPO and TG genes (15 % and 15 %, respectively); 41.1 % of these were variants of uncertain significance (VUS), 26.4 % were pathogenic, 23.5 % were likely benign, and 11.7 % were likely pathogenic. On the basis of their zygosity, we identified 73.5 % heterozygous, 17.6 % homozygous, and 8.9 % combined heterozygous variants. There were mutant variants in two genes in six patients and three in one patient.
CONCLUSIONS: This study found a variant in 55 % of the patients and shed light on the etiology of some cases of CH. The frequency of VUS was high. Although variants were identified in this study, their implication in the etiology of CH is not certain and, for most of the patients, it is also not sufficient for explaining the pathology with the current state of knowledge.
METHODS: A total of 52 patients (47 families) diagnosed with CH were included in the study. Overall, 32 target genes involved in thyroid physiology were investigated by next-generation sequencing (NGS).
RESULTS: In total, 29 (55 %) of the patients were male, and the rate of dysgenesis was 19.2 %. In this study, 29 of 52 patients had at least one variant in one gene involved in CH (n = 29, 33 different variants) (Including likely benign variants and variants of unknown significance). There were 21 patients (40.3 %) with gland in situ. The most common variant was DUOX2 (20 %). The second most common variants were those in the TPO and TG genes (15 % and 15 %, respectively); 41.1 % of these were variants of uncertain significance (VUS), 26.4 % were pathogenic, 23.5 % were likely benign, and 11.7 % were likely pathogenic. On the basis of their zygosity, we identified 73.5 % heterozygous, 17.6 % homozygous, and 8.9 % combined heterozygous variants. There were mutant variants in two genes in six patients and three in one patient.
CONCLUSIONS: This study found a variant in 55 % of the patients and shed light on the etiology of some cases of CH. The frequency of VUS was high. Although variants were identified in this study, their implication in the etiology of CH is not certain and, for most of the patients, it is also not sufficient for explaining the pathology with the current state of knowledge.
摘要：
目的：先天性甲状腺功能减退症（CH）是新生儿最常见的内分泌疾病；每3000-4000例新生儿中可见。遗传特征可以指导原位腺体患者的治疗。本研究旨在为CH变异的文献做出贡献，并显示遗传分析可以为随访患者提供的益处。
方法：本研究共纳入52例（47个家庭）确诊为CH的患者。总的来说,通过下一代测序（NGS）研究了32个与甲状腺生理有关的靶基因。
结果：总计，29例（55%）患者为男性，发育不全的发生率为19.2%。在这项研究中,52名患者中有29名患者在涉及CH的一个基因中至少有一个变异（n=29，33种不同的变异）（包括可能的良性变异和未知意义的变异）。原位腺体21例(40.3%)。最常见的变异体是DUOX2(20%)。第二个最常见的变异是TPO和TG基因（15%和15%，分别)；其中41.1%是不确定显著性变异(VUS)，26.4%为致病性，23.5%可能是良性的，11.7%可能致病。根据他们的接合性，我们鉴定出73.5%杂合，17.6%纯合,和8.9%的组合杂合变体。6例患者中的2个基因存在突变变异，1例患者中的3个基因存在突变变异。
结论：本研究在55%的患者中发现了变异，并阐明了部分CH病例的病因。VUS的频率很高。尽管在这项研究中发现了变异，它们在CH病因中的含义尚不确定，对于大多数患者来说，用目前的知识状态来解释病理学也是不够的。
方法：本研究共纳入52例（47个家庭）确诊为CH的患者。总的来说,通过下一代测序（NGS）研究了32个与甲状腺生理有关的靶基因。
结果：总计，29例（55%）患者为男性，发育不全的发生率为19.2%。在这项研究中,52名患者中有29名患者在涉及CH的一个基因中至少有一个变异（n=29，33种不同的变异）（包括可能的良性变异和未知意义的变异）。原位腺体21例(40.3%)。最常见的变异体是DUOX2(20%)。第二个最常见的变异是TPO和TG基因（15%和15%，分别)；其中41.1%是不确定显著性变异(VUS)，26.4%为致病性，23.5%可能是良性的，11.7%可能致病。根据他们的接合性，我们鉴定出73.5%杂合，17.6%纯合,和8.9%的组合杂合变体。6例患者中的2个基因存在突变变异，1例患者中的3个基因存在突变变异。
结论：本研究在55%的患者中发现了变异，并阐明了部分CH病例的病因。VUS的频率很高。尽管在这项研究中发现了变异，它们在CH病因中的含义尚不确定，对于大多数患者来说，用目前的知识状态来解释病理学也是不够的。
