Next-generation sequencing analysis of TSHR in 384 Chinese subclinical congenital hypothyroidism (CH) and CH patients

Abstract Background 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. Methods 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). Results 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. Conclusion 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.