DUOX2 and DUOXA2 Variants Confer Susceptibility to Thyroid Dysgenesis and Gland-in-situ With Congenital Hypothyroidism

Abstract

Background: Thyroid dysgenesis (TD), which is caused by gland developmental abnormalities, is the most common cause of congenital hypothyroidism (CH). In addition, advances in diagnostic techniques have facilitated the identification of mild CH patients with a gland-in-situ (GIS) with normal thyroid morphology. Therefore, TD and GIS account for the vast majority of CH cases. Methods: Sixteen known genes to be related to CH were sequenced and screened for variations by next-generation sequencing (NGS) in a cohort of 377 CH cases, including 288 TD cases and 89 GIS cases. Results: In our CH cohort, we found that DUOX2 (21.22%) was the most commonly variant pathogenic gene, while DUOXA2 was prominent in TD (18.75%) and DUOX2 was prominent in GIS (34.83%). Both biallelic and triple variants of DUOX2 were found to be most common in children with TD and children with GIS. The most frequent combination was DUOX2 with DUOXA1 among the 61 patients who carried digenic variants. We also found for the first time that biallelic TG, DUOXA2, and DUOXA1 variants participate in the pathogenesis of TD. In addition, the variant p.Y246X in DUOXA2 was the most common variant hotspot, with 58 novel variants identified in our study. Conclusion: We meticulously described the types and characteristics of variants from sixteen known gene in children with TD and GIS in the Chinese population, suggesting that DUOXA2 and DUOX2 variants may confer susceptibility to TD and GIS via polygenic inheritance and multiple factors, which further expands the genotype-phenotype spectrum of CH in China.

Analysis of Mutation Spectra of 28 Pathogenic Genes Associated With Congenital Hypothyroidism in the Chinese Han Population

“…The screening showed that the gene mutation detection rate was 93.33%, and was mainly detected in genes that affect thyroid hormone synthesis, such as DUOX2, TPO, and TG. Previous studies have shown that the detection rate of DUOX2 mutations in children with CH in China is as high as 28%-44%, whereas the detection rate obtained in this study was 44%, suggesting that DUOX2 mutations may be the160 main cause of CH in the Chinese population (22)(23)(24). DUOX2 is mainly involved in the production of peroxide protein complexes and catalyzes the synthesis of thyroid hormones in thyroid follicular cells (25).…”

Thyroid Gene Mutations in Pregnant and Breastfeeding Women Diagnosed With Transient Congenital Hypothyroidism: Implications for the Offspring’s Health

“…sequence 16 genes related with CH by next-generation sequence (NGS) in 377 CH patients and found patients with biallelic mutations in DUOX2 and DUOXA1, suggesting that DUOX1 and DUOXA1 could also play a role in thyroid hormone synthesis (49). TPO is responsible for iodide organification and the coupling of tyrosyl residues, essential steps in thyroid hormone synthesis (50).…”

Combining whole-exome sequencing with clinical data for genotype–phenotype correlation in patients with congenital hypothyroidism that include the DUOX2 gene variation

“…Moreover, the DUOX2 gene located on chromosome 15 is constantly reported as a disease-causing gene in CH. It has been con rmed that an inadequate DUOX2-derived H 2 O 2 supply is closely linked to DH in murine models [13,14,15]. Recently, Chopra et al [16] found that the mutation of a single DUOX gene resulted in a phenotype-associated hypothyroidism in zebra sh, including growth retardation and goiter.…”