Variant Screening and Phenotype Analysis in 367 Chinese Patients With Congenital Hypothyroidism.

Background: Genetic defects in the human thyroid-stimulating hormone (TSH) receptor () gene can cause congenital hypothyroidism (CH). However, the biological functions and comprehensive genotype-phenotype relationships for most variants associated with CH remain unexplored. We aimed to identify variants in Chinese patients with CH, analyze the functions of the variants, and explore the relationships between genotypes and clinical phenotypes.

Methods: In total, 367 patients with CH were recruited for variant screening using whole-exome sequencing. The effects of the variants were evaluated by programs such as SIFT and polyphen2. Furthermore, these variants were transfected into 293T cells to detect their Gs/cyclic AMP and Gq/11 signaling activity.

Results: Among the 367 patients with CH, 17 variants, including three novel variants, were identified in 45 patients, and 18 patients carried biallelic variants. experiments showed that 10 variants were associated with Gs/cyclic AMP and Gq/11 signaling pathway impairment to varying degrees. Patients with biallelic variants had lower serum TSH levels and higher free triiodothyronine and thyroxine levels at diagnosis than those with biallelic variants.

Conclusions: We found a high frequency of variants in Chinese patients with CH (12.3%), and 4.9% of cases were caused by biallelic variants. Ten variants were identified as loss-of-function variants. The data suggest that the clinical phenotype of CH patients caused by biallelic variants is relatively mild. Our study expands the variant spectrum and provides further evidence for the elucidation of the genetic etiology of CH.