Molecular and clinical genetics of the transcription factor GLIS3 in Chinese congenital hypothyroidism.

The transcription factor GLIS3 is an important factor in hormone biosynthesis and thyroid development, and mutations in GLIS3 are relatively rare. Deletions of more than one of the 11 exons of GLIS3 occur in most patients with various extrathyroidal abnormalities and congenital hypothyroidism (CH), and only 18 missense variants of GLIS3 related to thyroid disease have been reported. The aim of this study was to report the family history and molecular basis of patients with CH who carry GLIS3 variants. Three hundred and fifty-three non-consanguineous infants with CH were recruited and subjected to targeted exome sequencing of CH-related genes. The transcriptional activity and cellular localization of the variants in GLIS3 were investigated in vitro. We identified 20 heterozygous GLIS3 exonic missense variants, including eight novel sites, in 19 patients with CH. One patient carried compound heterozygous GLIS3 variants (p.His34Arg and p.Pro835Leu). None of the variants affected the nuclear localization. However, three variants (p.His34Arg, p.Pro835Leu, and p.Ser893Phe) located in the N-terminal and C-terminal regions of the GLIS3 protein downregulated the transcriptional activation of several genes required for thyroid hormone (TH) biosynthesis. This study of patients with CH extends the current knowledge surrounding the spectrum of GLIS3 variants and the mechanisms by which they cause TH biosynthesis defects.