Targeted next-generation sequencing of thirteen causative genes in Chinese patients with congenital hypothyroidism

• Published in: Endocrine Journal Vol. 65; no. 10; pp. 1019 - 1028
• Main Authors: Long, Wei, Lu, Guanting, Zhou, Wenbai, Yang, Yuqi, Zhang, Bin, Zhou, Hong, Jiang, Lihua, Yu, Bin
• Format: Journal Article
• Language: English
• Published: Japan The Japan Endocrine Society 01.01.2018; Japan Science and Technology Agency
• Subjects: Adenosine Triphosphatases - genetics; Asian Continental Ancestry Group - genetics; Autoantigens - genetics; China; Chromogranins - genetics; Congenital diseases; Congenital hypothyroidism; Congenital Hypothyroidism - genetics; DNA sequencing; DNA-Binding Proteins - genetics; Dual Oxidases - genetics; Etiology; Gene mutation; GTP-Binding Protein alpha Subunits, Gs - genetics; High-Throughput Nucleotide Sequencing; Homeobox Protein Nkx-2.5 - genetics; Humans; Hypothyroidism; Iodide Peroxidase - genetics; Iron-Binding Proteins - genetics; Microfilament Proteins - genetics; Muscle Proteins - genetics; Mutation; Next-generation sequencing; Nkx2.5 protein; Pax8 protein; PAX8 Transcription Factor - genetics; Phenotype; Receptors, Thyrotropin - genetics; Thyroglobulin; Thyroid; Thyroid gland; Thyroid oxidase 2; Thyroid-stimulating hormone; Thyroid-stimulating hormone receptors; Transcription Factors - genetics; China; Next-generation sequencing; Thyroglobulin; Gene mutation; Congenital hypothyroidism; Thyroid oxidase 2
• ISSN: 0918-8959; 1348-4540
• DOI: 10.1507/endocrj.EJ18-0156

To identify the spectrum and prevalence of thirteen causative genes mutations in congenital hypothyroidism (CH) patients, we collected blood samples and extracted genomic DNA of 106 CH patients, and designed a customized targeted next-generation sequencing panel containing 13 CH-causing genes to detect mutations. A total of 132 mutations were identified in 65.09% of patients (69/106) on the following nine genes: DUOX2, TG, TPO, TSHR, TTF1, TTF2, NKX2-5, PAX8 and GNAS. 69.70% (92/132) mutations related to thyroid dyshormonogenesis genes, including DUOX2 (n = 49), TG (n = 35), and TPO (n = 8). 21.21% (28/132) mutations related to thyroid dysgenesis genes, including TSHR (n = 19), TTF1 (n = 5), TTF2 (n = 1), PAX8 (n = 2), and NKX2-5 (n = 1). 9.09% (12/132) mutations related to GNAS, which was associated with thyrotropin resistance. No mutation of THRA, TSHB, IYD or SLC5A5 was detected. Among 69 mutations detected patients, 41 (59.42%) patients were two or more mutations detected, and mutations of 30 (43.48%) patients related to two or three genes. According to the pathomechanism of the mutant genes, 57.97% CH patients were classified as thyroid dyshormonogenesis. Overall, DUOX2, TG and TSHR mutations were the most common genetic defects in Chinese CH patients, and thyroid dyshormonogenesis could be the first genetic etiology of CH in Chinese. Besides, multiple mutations accounts for a part of genetic pathogenesis.