Genetic screening and functional characterization of DUOX2 mutations in patients with congenital hypothyroidism

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Abstract Context Congenital hypothyroidism (CH) is the most prevalent endocrine disorders detected via newborn screening. Variants in dual oxidase 2 (DUOX2) have been established as a major genetic contributor to CH in Chinese populations. Objective To characterize the genetic spectrum of DUOX2 variants and explore their clinical correlations in a cohort of CH patients from Fujian Province, China, and to assess variant impact on enzymatic activity. Methods We enrolled 184 Han Chinese CH patients. DUOX2 variants were screened via exome sequencing. Clinical data (thyroid function, ultrasonography) were integrated with in vitro measurement of H2O2 generation for selected variants. Results Of the 184 patients, 114 (61.96%) carried genetic variants. DUOX2 was the most prevalent, accounting for 43.48% (80/184) of cases. Notably, statistically significant differences in TSH, FT4, and FT3 levels were observed between DUOX2 variant carriers and noncarriers. Ultrasonography revealed that normal thyroid morphology was the predominant finding in children with DUOX2 variants. In vitro functional assays revealed that 5 out of 11 DUOX2 variants exhibited significantly impaired H2O2 production capacity. Notably, variants in both functional and unstructured domains impaired residual enzymatic activity. Conclusion DUOX2 is the most common causative gene for CH in the Fujian cohort, and its variants are associated with a more severe biochemical phenotype at onset diagnosis. Functional heterogeneity suggests that impaired enzymatic activity is a key, but not exclusive, pathogenetic mechanism. Ultimately our findings highlight the critical need for integrating genetic and functional analyses into the clinical management and genetic counseling of CH.

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