The Core Laboratory in Medical Center of Clinical Research, Department of Endocrinology, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Department of Endocrinology, Maternal and Child Health Institute of Bozhou, Bozhou, China.
Eur J Endocrinol. 2018 Jun;178(6):623-633. doi: 10.1530/EJE-17-1017. Epub 2018 Apr 12.
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.
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.
Our results showed that 57 patients (51.82%) carried biallelic mutations (containing compound heterozygous mutations and homozygous mutations) in six genes (, , , , and ) involved in thyroid hormone synthesis. Autosomal recessive inheritance of CH caused by mutations in , , and was confirmed by analysis of 22 family pedigrees. Notably, eight mutations in four genes (, , and ) 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.
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 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.
先天性甲状腺功能减退症（CH）是最常见的新生儿代谢紊乱，其特征是神经发育受损。尽管已有多个候选基因与 CH 相关，但对致病基因的全面筛查仍受到限制。
本研究纳入了 110 例原发性 CH 患者。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。通过对家系图谱的研究分析了致病基因的遗传模式。
我们的结果显示，在 6 个参与甲状腺激素合成的基因（、、、、和）中，有 57 例患者（51.82%）携带双等位基因突变（包含复合杂合突变和纯合突变）。通过对 22 个家系图谱的分析，证实了由、、和基因突变引起的 CH 呈常染色体隐性遗传。值得注意的是，在 8 例患者中发现了四个基因（、、和）中的 8 个突变，这些突变导致甲状腺发育不良。这些突变在所有病例中均为杂合子，且这些患者的父母均未观察到甲状腺功能减退。
中国大多数先天性甲状腺功能减退症病例是由甲状腺激素生成障碍引起，而不是甲状腺发育不良。本研究在 110 例中国患者中发现了先前报道的致病基因，并揭示在这些患者中最常突变的基因为。本研究扩展了中国 CH 患者的基因突变谱，与西方国家存在显著差异。
