The genetic characteristics of congenital hypothyroidism in China by comprehensive screening of 21 candidate genes.
The genetic characteristics of congenital hypothyroidism in China by comprehensive screening of 21 candidate genes.
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综合筛选21个候选基因分析中国先天性甲状腺功能减退症的遗传特征
DOI：
10.1530/eje-17-1017
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发表时间：
2018-06
影响因子：
5.8
通讯作者：
Song HD
中科院分区：
文献类型：
--
作者：
Sun F;Zhang JX;Yang CY;Gao GQ;Zhu WB;Han B;Zhang LL;Wan YY;Ye XP;Ma YR;Zhang MM;Yang L;Zhang QY;Liu W;Guo CC;Chen G;Zhao SX;Song KY;Song HD
目的先天性甲状腺功能减退症（CH）是新生儿最常见的代谢性疾病，以神经发育受损为特征。虽然已经有几个候选基因与CH相关，但对致病基因的全面筛选一直受到限制。研究设计与方法：110例原发性CH患者纳入本研究。通过下一代测序分析了21个CH候选基因的所有外显子和外显子-内含子边界。通过家系调查分析致病基因的遗传方式。结果57例（51.82%）患者存在与甲状腺激素合成有关的6个基因（DUOX 2、DUOXA 2、DUOXA 1、TG、TPO和TSHR）的双等位基因突变（包括复合杂合突变和纯合突变）。通过对22个家系的分析，证实CH是由DUOX 2、DUOXA 2、TG和TPO基因突变引起的常染色体隐性遗传。值得注意的是，在8个先证者中发现了4个基因（FOXE 1，NKX 2 -1，PAX 8和HHEX）中的8个突变，这些突变导致甲状腺发育不全。这些突变在所有病例中均为杂合子，在这些先证者的父母中未观察到甲状腺功能减退。结论我国先天性甲状腺功能减退症多为甲状腺激素生成障碍所致，而非甲状腺发育不良。这项研究确定了先前报道的57/110例中国患者的致病基因，并发现DUOX 2是这些患者中最常见的突变基因。我们的研究扩大了中国患者的CH突变谱，这与西方国家有显著差异。
Objective Congenital hypothyroidism (CH), the most common neonatal metabolic disorder, is characterized by impaired neurodevelopment. Although several candidate genes have been associated with CH, comprehensive screening of causative genes has been limited. Design and methods One hundred ten patients with primary CH were recruited in this study. All exons and exon–intron boundaries of 21 candidate genes for CH were analyzed by next-generation sequencing. And the inheritance pattern of causative genes was analyzed by the study of family pedigrees. Results Our results showed that 57 patients (51.82%) carried biallelic mutations (containing compound heterozygous mutations and homozygous mutations) in six genes (DUOX2, DUOXA2, DUOXA1, TG, TPO and TSHR) involved in thyroid hormone synthesis. Autosomal recessive inheritance of CH caused by mutations in DUOX2, DUOXA2, TG and TPO was confirmed by analysis of 22 family pedigrees. Notably, eight mutations in four genes (FOXE1, NKX2-1, PAX8 and HHEX) that lead to thyroid dysgenesis were identified in eight probands. These mutations were heterozygous in all cases and hypothyroidism was not observed in parents of these probands. Conclusions Most cases of congenital hypothyroidism in China were caused by thyroid dyshormonogenesis rather than thyroid dysgenesis. This study identified previously reported causative genes for 57/110 Chinese patients and revealed DUOX2 was the most frequently mutated gene in these patients. Our study expanded the mutation spectrum of CH in Chinese patients, which was significantly different from Western countries.