Common and Rare DUOX Variants in Patients With Congenital Hypothyroidism: Case-control Study and Family-based Analysis.

Context: Dual oxidases (DUOXs) are essential for thyroid hormone synthesis. Rare DUOX variations have been detected in patients with congenital hypothyroidism (CH); however, their mode of inheritance and genotype-phenotype correlations remain unclear. Additionally, no study has determined whether common DUOX variants confer a risk of CH.

Objective: To elucidate the molecular and clinical characteristics of CH caused by rare and common DUOX variants.

Methods: Targeted next-generation sequencing was performed on 203 trios (parents and their child with CH) to screen for rare DUOX variants. For common variants, 8 tag single nucleotide polymorphisms (SNPs) were genotyped among 298 trios and 439 healthy controls. The association between these SNPs and CH risk was analyzed using a case-control study and a family-based transmission disequilibrium test.

Results: The genetic contribution of rare DUOX variants to CH was 16.3% (DUOX2 14.3% and DUOXA2 2.0%). Familial cosegregation analysis suggested that DUOX variants were transmitted by an autosomal recessive pattern. These patients exhibited dyshormonogenesis and were more likely to develop into transient CH with the lower requirement of levothyroxine dose. Regarding common variants, 5 SNPs distributed across DUOXs were significantly associated with CH in both the case-control and family-based study. DUOX1 rs16939752 C > T and DUOXA1 rs3784576 C > A protected against CH, whereas DUOX2 rs269868 A > G, rs2001616 A > G and DUOXA2 rs2252371 T > C were associated with increased susceptibility to CH.

Conclusion: Our research confirmed that DUOX variants are inherited in an autosomal recessive manner. We present a comprehensive spectrum of rare and common DUOX variants that provides more accurate insights into the pathogenesis of CH associated with DUOX.