Department of Genetic Metabolism, Children's Hospital, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning 530003, People's Republic of China; GuangXi Center for Birth Defects Research and Prevention, Nanning 530003, People's Republic of China.
Department of Genetic Metabolism, Children's Hospital, Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, Nanning 530003, People's Republic of China; Boston Children's Hospital, Harvard Medical School, Boston 02115, MA, United States.
Clin Chim Acta. 2016 Nov 1;462:127-132. doi: 10.1016/j.cca.2016.09.007. Epub 2016 Sep 13.
Defects in the human TSHR gene are reported to be one of the causes of CH due to thyroid dysgenesis, the purpose of this study was to examine the TSHR mutation spectrum and prevalence in congenital hypothyroidism (CH) and subclinical congenital hypothyroidism (SCH) patients in the Guangxi Zhuang Autonomous Region of China and to evaluate the genotype-phenotype correlations.
Blood samples were collected from 384 patients including 240 CH and 144 SCH patients in Guangxi, China. Genomic DNA was extracted from peripheral blood leukocytes. All exons of the 11 known CH associated genes including TSHR together with their exon-intron boundaries were screened by next-generation sequencing (NGS).
NGS analysis of TSHR revealed nine different variants in ten individuals. Six (4.2%) of 144 patients with SCH were found to harbor monoallelic TSHR variants. Four (1.6%) of 240 patients with CH harbored TSHR variants combined with another monoallelic mutation in either DUOX2 or TG gene. The present study identified five novel variants c.1838A>G (p.Y613C), c.1576G>A (p.A526T), c.2087T>G (p.F696C), c.1631G>A (p.G544E) and c.2051C>A (p.A684D) in TSHR, seven known pathogenic variants c.1349G>A (p.R450H), c.326G>A (p.R109Q), c.2066T>G (p.V689G) and c.2272G>A (p.E758K) in TSHR, IVS3+2T>G in TG, and c.1588A>T (p.K530X) and c.2635G>A (p.E879K) in DUOX2. The previously reported hotspot mutation p.R450H was found in only one SCH patient.
The prevalence of TSHR mutations was 1.6% in CH patients and 4.2% in SCH patients in Guangxi Zhuang Autonomous Region of China. Monoallelic TSHR pathogenic variants were associated with SCH, while TSHR pathogenic variants combined with monoallelic mutations in DUOX2 or TG gene might contribute to CH. Our study expands the TSHR mutation spectrum and provides the best estimation of mutation rate for SCH and CH patients in this Chinese population.
据报道，人类 TSHR 基因的缺陷是甲状腺发育不全导致先天性甲状腺功能减退症（CH）的原因之一。本研究旨在检测中国广西地区先天性甲状腺功能减退症（CH）和亚临床先天性甲状腺功能减退症（SCH）患者 TSHR 突变谱和突变率，并评估基因型-表型相关性。
收集了来自中国广西的 384 名患者的血样，包括 240 名 CH 患者和 144 名 SCH 患者。从外周血白细胞中提取基因组 DNA。通过下一代测序（NGS）对 11 个已知的与 CH 相关的基因（包括 TSHR）的所有外显子及其内含子边界进行了筛选。
TSHR 的 NGS 分析在 10 个人中发现了 9 种不同的变体。在 144 名 SCH 患者中，有 6 名（4.2%）携带单等位基因 TSHR 变体。在 240 名 CH 患者中，有 4 名（1.6%）携带 TSHR 变体，同时在 DUOX2 或 TG 基因中携带另一个单等位基因突变。本研究在 TSHR 中鉴定了 5 个新的变体 c.1838A>G（p.Y613C）、c.1576G>A（p.A526T）、c.2087T>G（p.F696C）、c.1631G>A（p.G544E）和 c.2051C>A（p.A684D），7 个已知的致病性变体 c.1349G>A（p.R450H）、c.326G>A（p.R109Q）、c.2066T>G（p.V689G）和 c.2272G>A（p.E758K）在 TSHR 中，IVS3+2T>G 在 TG 中，c.1588A>T（p.K530X）和 c.2635G>A（p.E879K）在 DUOX2 中。先前报道的热点突变 p.R450H 仅在 1 名 SCH 患者中发现。
在中国广西地区，CH 患者 TSHR 突变率为 1.6%，SCH 患者为 4.2%。单等位基因 TSHR 致病性变体与 SCH 相关，而 TSHR 致病性变体与 DUOX2 或 TG 基因的单等位基因突变相结合可能导致 CH。本研究扩展了 TSHR 突变谱，并为中国人群中 SCH 和 CH 患者的突变率提供了最佳估计。
