Dual Oxidase System Genes Defects in Children With Congenital Hypothyroidism

The objectives of this study were to analyze the distribution of dual oxidase (DUOX) system genes (containing DUOX2, DUOX1, DUOXA2, and DUOXA1) variants in children with congenital hypothyroidism (CH) and their phenotypes.

Target region sequencing technology was performed on DUOX system genes among 606 CH subjects covering all the exon and intron regions. Detailed clinical data were collected for statistical analysis.

A total of 95 suspected pathogenic variants were detected in the DUOX system genes, showing a 39.11% rate in variant carrying (237/606). DUOX2 had the highest rate in this study. There were statistical differences in maximum adjusted dose and current dose of levothyroxine between the DUOX system genes nonmutated group with the mutated group (both Ps < 0.001). The cases in the DUOX system genes mutated group were more likely to develop into transient CH (χ 2 = 23.155, P < 0.001) and more likely to manifested as goiter or gland-in-situ (χ 2 = 66.139, P < 0.001). In addition, there was no significant difference in clinical characteristics between DUOX system genes monoallelic and non-monoallelic. Although 20% of the variants affected the functional domain regions (EF hand, flavin adenine dinucleotide and nicotinamide adenine dinucleotide binding sites), there was no significant effect on the phenotype severity whether the variation is located in the functional domain regions.

Our results showed the high variation rate of DUOX2 in the DUOX system genes among Chinese CH patients. The complex genotype-phenotype relationship of DUOX system genes broadened the understanding of CH phenotype spectrum.