Large-scale screening and functional study of DUOXA2 variant in 599 Chinese patients with congenital hypothyroidism.

Objective: Dual oxidase maturation factor 2 (DUOXA2) is necessary for proper cellular localization and maturation of functional dual oxidase 2 (DUOX2). It is an attractive candidate gene for congenital hypothyroidism (CH). This study aimed to identify DUOXA2 variants in Chinese CH patients, analyze the function of the variants, and explore the genotype-phenotype relationship.

Design: A total of 599 patients with CH were recruited for screening DUOXA2 variants by performing targeted next-generation sequencing or whole exome sequencing. Detailed clinical data were collected for statistical analysis. The biological function of the identified DUOXA2 variants was detected in vitro.

Results: A total of 13 variants including 6 novel variants were detected in the DUOXA2 gene, showing a 6.7% rate in variant carrying (40/599). Ten variants disrupted the enzyme activity of DUOX2, resulting in impaired H2O2 production. In addition, we found that oligogenic mutation patterns within the DUOX system were prevalent among Chinese patients with CH. The cases in the DUOXA2-mutated group were milder and more likely to manifest as normal thyroid size than those in the nonmutated group.

Conclusions: Our study greatly expanded the variant spectrum of the DUOXA2 gene. Pedigree and in vitro functional studies improved the accuracy of genetic counseling. The genotype-phenotype relationship of DUOXA2 broadened the understanding of the CH phenotype spectrum.