Molecular and clinical characteristics of congenital hypothyroidism in a large cohort study based on comprehensive thyroid transcription factor mutation screening in Henan

Background: Congenital hypothyroidism (CH), the most common neonatal endocrine disorder worldwide, can be caused by variants in thyroid transcription factor (TTF) genes including NKX2-1, FOXE1, PAX8, NKX2-5 and HHEX. This study aims to perform targeted next-generation sequencing (NGS) panel for comprehensive mutation screening on these genes in a cohort of 606 CH patients with various types from Henan Province, China, to investigate the mutation rate of TTF genes, and to analyze the clinical, biochemical and molecular characteristics of our CH cohort. Methods: High-throughput sequencing combined with statistical calculation were applied for mutation screening and analyses of the clinical data. Results: Twenty-two likely disease-causing monoallelic mutations in the TTF genes were identified in our cohort (3.63%, 22/606). Mutated PAX8 was the most predominant genetic alteration among these TTF mutations. Interestingly, PAX8 defects were only found in TD cases and variants in the five TTF genes were detected in gland in situ (GIS) patients. CH patients with the same genotype may have significant phenotypic variability and permanent CH (PCH) patients in the GIS group were significantly fewer than those in the TD group. Conclusions: Our study showed the estimated TTF mutation rate among CH cases was 3.63% in Henan Province and genetic alternations in TTF genes played a role not only in TD but also in GIS, especially in goiter. Although we speculated that the five TTF genes may be involved in certain steps of thyroid hormone biosynthesis, more researches are needed to verify the conclusions of the present study.

Automated summary

A study in Henan Province, China found a mutation rate of 3.63% in TTF genes among congenital hypothyroidism (CH) cases, with mutated PAX8 being the most predominant genetic alteration. Patients with the same genotype may exhibit significant phenotypic variability, indicating that genetic alternations in TTF genes play a role not only in TD but also in GIS.