Patients with Thyroid Dyshormonogenesis and DUOX2 Variants: Molecular and Clinical Description and Genotype-Phenotype Correlation

Abstract

Thyroid dyshormonogenesis (THD) is a heterogeneous group of genetic diseases caused by the total or partial defect in the synthesis or secretion of thyroid hormones. Genetic variants in DUOX2 can cause partial to total iodination organification defects and clinical heterogeneity, from transient to permanent congenital hypothyroidism. The aim of this study was to undertake a molecular characterization and genotype-phenotype correlation in patients with THD and candidate variants in DUOX2. A total of 31 (19.38%) patients from the Catalan Neonatal Screening Program presented with variants in DUOX2 that could explain their phenotype. Fifteen (48.39%) patients were compound heterozygous, 10 (32.26%) heterozygous, and 4 (12.90%) homozygous. In addition, 8 (26.67%) of these patients presented variants in other genes. A total of 35 variants were described, 10 (28.57%) of these variants have not been previously reported in literature. The most frequent variant in our cohort was c.2895_2898del/p.(Phe966SerfsTer29), classified as pathogenic according to reported functional studies. The final diagnosis of this cohort was permanent THD in 21 patients and transient THD in 10, according to reevaluation and/or need for treatment with levothyroxine. A clear genotype-phenotype correlation could not be identified; therefore, functional studies are necessary to confirm the pathogenicity of the variants.

Keywords: CH; DUOX2; congenital hypothyroidism; dual oxidase 2; phenotypic variability; thyroid dyshormonogenesis.

Figure 1

Diagram of DUOX2 gene and protein. (a) DUOX2 gene (NG_009447.1) with boxes indicating the 34 exons (e1–e34). The coding sequence (CDS) from e2 to e34 (NM_014080.5) codifies for the DUOX2 protein. The dashed lines indicate the intronic DUOX2 variants described in our cohort that explained the phenotype of patients. (b) DUOX2 protein (NP_054799) with the corresponding functional domains (colored boxes). The dashed lines indicate the localization of the exonic variants detected in our cohort.