Dataset Information

DUOX2 variants are a frequent cause of congenital primary hypothyroidism in Thai patients.

ABSTRACT:

Objective

To identify the genetic etiologies of congenital primary hypothyroidism (CH) in Thai patients.

Design and methods

CH patients were enrolled. Clinical characteristics including age, signs and symptoms of CH, pedigree, family history, screened thyroid-stimulating hormone results, thyroid function tests, thyroid imaging, clinical course and treatment of CH were collected. Clinical exome sequencing by next-generation sequencing was performed. In-house gene list which covered 62 potential candidate genes related to CH and thyroid disorders was developed for targeted sequencing. Sanger sequencing was performed to validate the candidate variants. Thyroid function tests were determined in the heterozygous parents who carried the same DUOX2 or DUOXA2 variants as their offsprings.

Results

There were 118 patients (63 males) included. Mean (SD) age at enrollment was 12.4 (7.9) years. Forty-five of 118 patients (38%) had disease-causing variants. Of 45 variants, 7 genes were involved (DUOX2, DUOXA2, TG, TPO, SLC5A5, PAX8 and TSHR). DUOX2, a gene causing thyroid dyshormonogenesis, was the most common defective gene (25/45, 56%). The most common DUOX2 variant found in this study was c.1588A>T. TG and TPO variants were less common. Fourteen novel variants were found. Thyroid function tests of most parents with heterozygous state of DUOX2 and DUOXA2 variants were normal.

Conclusions

DUOX2 variants were most common among Thai CH patients, while TG and TPO variants were less common. The c.1588A>T in DUOX2 gene was highly frequent in this population.

SUBMITTER: Sorapipatcharoen K

PROVIDER: S-EPMC7774760 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Publications

DUOX2 variants are a frequent cause of congenital primary hypothyroidism in Thai patients.

Sorapipatcharoen Kinnaree K Tim-Aroon Thipwimol T Mahachoklertwattana Pat P Chantratita Wasun W Iemwimangsa Nareenart N Sensorn Insee I Panthan Bhakbhoom B Jiaranai Poramate P Noojarern Saisuda S Khlairit Patcharin P Pongratanakul Sarunyu S Suprasongsin Chittiwat C Korwutthikulrangsri Manassawee M Sriphrapradang Chutintorn C Poomthavorn Preamrudee P

Endocrine connections 20201101 11

<h4>Objective</h4>To identify the genetic etiologies of congenital primary hypothyroidism (CH) in Thai patients.<h4>Design and methods</h4>CH patients were enrolled. Clinical characteristics including age, signs and symptoms of CH, pedigree, family history, screened thyroid-stimulating hormone results, thyroid function tests, thyroid imaging, clinical course and treatment of CH were collected. Clinical exome sequencing by next-generation sequencing was performed. In-house gene list which covered ...[more]

PMID: 33310921

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Project description:Background: The etiology, course, and most appropriate management of borderline congenital hypothyroidism (CH) are poorly defined, such that the optimal threshold for diagnosis with bloodspot screening thyrotropin (bsTSH) measurement remains controversial. Dual oxidase 2 (DUOX2) mutations may initially cause borderline elevation of bsTSH, which later evolves into significant hypothyroidism on venous blood measurement. It was hypothesized that mutations in both DUOX2 and its accessory protein DUOXA2 may occur frequently, even in patients with borderline bsTSH elevation, such that higher diagnostic thresholds in bsTSH screening may fail to detect such cases, with consequent risk of undiagnosed neonatal hypothyroidism of sufficient magnitude to require thyroxine therapy. This study aimed to investigate the frequency and characteristics of DUOX2 and DUOXA2 mutations in a borderline CH cohort. Methods: A cross-sectional study of patients with borderline CH was undertaken at Great Ormond Street Hospital, a tertiary British pediatric center. DUOX2 was sequenced in 52 patients with a bsTSH of 6-19.9 mIU/L, venous TSH of >25 mIU/L, and eutopic thyroid gland in situ. DUOXA2 was sequenced in DUOX2 mutation-negative cases, and novel DUOXA2 mutations were functionally characterized. Results: A total of 26 (50%) patients harbored likely pathogenic mutations in DUOX2 (n = 20; 38%) or DUOXA2 (n = 6; 12%), including novel gene variants (DUOX2, n = 3; DUOXA2, n = 7). Two recurrent DUOX2 mutations (p.Q570L, p.F966Sfs*29) occurred frequently in population databases (MAF ≥0.01). Despite bsTSH being <10 mIU/L in 46% of DUOX2 and DUOXA2 mutation-positive cases, venous free thyroxine levels in these patients were in the moderate CH range (M = 9.3 pmol/L, range <3.9-15.8 pmol/L), Conclusions: Targeted DUOX2 and DUOXA2 sequencing in a borderline CH cohort has a high diagnostic yield. These findings might argue for a lowering of bsTSH thresholds, but follow-up studies are required to assess whether cases with borderline bsTSH harboring DUOX2/DUOXA2 mutations will benefit from an early diagnosis and subsequent levothyroxine treatment.

Dataset Information

DUOX2 variants are a frequent cause of congenital primary hypothyroidism in Thai patients.

Objective

Design and methods

Results

Conclusions

Publications

DUOX2 variants are a frequent cause of congenital primary hypothyroidism in Thai patients.

Similar Datasets

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