DUOX2 Mutations Are Frequently Associated With Congenital Hypothyroidism in the Korean Population

Abstract

BackgroundMost cases with congenital hypothyroidism (CH) are usually sporadic, while about 20% of the cases are caused by genetic defects. Little information is available regarding the mutation incidence and genetic heterogeneity of CH in Koreans. We aimed to determine the mutation incidence of CH in newborn screenings (NBS) and to evaluate the frequency and spectrum of mutations underlying CH.MethodsA total of 112 newborns with thyroid dysfunction were enrolled from 256,624 consecutive NBS. Furthermore, 58 outpatients with primary CH were added from an endocrine clinic. All coding exons of TSHR, PAX8, TPO, DUOX2, DUOXA2, and SCL5A5 were sequenced.ResultsThe mutation incidence of CH was estimated to be 1 in 6,580 newborns. A total of 36 different mutations were identified in 53 cases. The overall mutation positive rate was 31%. The DUOX2 mutations were the most prevalent in both newborns and outpatients. Seven different recurrent mutations [p.G488R (n=13), p.A649E (n=3), p.R885Q (n=3), p.I1080T (n=2), and p.A1206T (n=2) in DUOX2; p.Y138X (n=9) in DUOXA2; and p.R450H (n=5) in TSHR) were identified as the mutations underlying CH.ConclusionsThe mutation incidence of CH was considerably higher than expected in the Korean newborn population. This study revealed seven different recurrent mutations underlying CH. We conclude that DUOX2 mutations are a frequent cause of CH in the Korean population.

DUOX2 Gene Mutation Manifesting as Resistance to Thyrotropin Phenotype

“…We Table 1) to be deleterious and has been previously reported to be associated with congenital hypothyroidism (2,3). The father was heterozygous for one of the mutations (p.R885L) while the mother had two (p.A649E and p.P1391A) (Fig.…”

Comprehensive Screening of Eight Known Causative Genes in Congenital Hypothyroidism With Gland-in-Situ

“…Previous genetic evaluations of cohorts of CH with GIS have been less comprehensive, screening fewer genes, or fewer cases with restricted ethnicities (6, 9, 22, 23). The only large-scale multiplex study in CH did not select cases on the basis of thyroid morphology and excluded TG, SLC26A4, and IYD from its sequencing panel (11). Direct sequencing of DUOX2, TG, TPO, and TSHR has been undertaken in 43 Korean CH cases with GIS (6); in common with our study, only around 50% of cases harbored causative, pathogenic variants in one or more genes.…”

“…Previous studies have generally focused on either a small number of genes (eg, TG, TPO, TSHR, and DUOX2 in 43 Korean cases) (6), specific phenotypic subsets of cases (5, 8), or multiple genes in a small subset of patients (9). There are occasional reports of digenic mutations involving TSHR and either DUOX2 (6, 10, 11) or TPO (12), or combined DUOX2 and DUOXA2 mutations (13). However, the role of oligogenicity in disease development and penetrance remains unclear, with no evidence for an additive effect of digenic mutations in one large published kindred (12).…”

“…A recent publication describes large-scale multiplexed genetic screening of TPO, TSHR, DUOX2, DUOXA2, PAX8, and SLC5A5 in 170 Korean CH cases. However, cases were from a single ethnic background and not selected on the basis of thyroid morphology; moreover TG, IYD, and SLC26A4 were not sequenced (11). We undertook comprehensive screening of TG, TPO, DUOX2, DUOXA2, IYD, SLC5A5 , SLC26A4, and TSHR in an ethnically and biochemically heterogeneous CH cohort with GIS.…”

Fetal Goitrous Hypothyroidism and Polyhydramnios in a Patient with Compound Heterozygous <b><i>DUOXA2</i></b> Mutations

“…Since then, a total of 7 patients have been reported [7, 14-18], and all reported patients were detected in the frame of newborn screening for CH, although available clinical information is limited [17]. Here, we report the first DUOXA2 mutation-carrying patient presenting with a marked fetal goiter and thus was noticed to have a thyroid abnormality prenatally.…”