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

Abstract

Objective: To identify 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.

Genetic and Phenotypic Characteristics of Congenital Hypothyroidism in a Chinese Cohort

“…However, patients with normal-sized GIS accounted for the majority of the cases in our cohort. Meanwhile, the frequency of genetic defects in the genes causing DH was higher than that in the genes causing TD, which was in agreement with previous studies in China and other Asian countries (11)(12)(13). These studies suggested that DH might be the leading pathophysiology of CH in Chinese populations, in contrast to what has been reported in other populations.…”

“…The higher frequency of variants in DUOX2 was consistent with the observation of a higher proportion of DH cases in our participants. Variants in DUOX2 have been frequently reported, especially in East Asia (11)(12)(13)(14). Several studies have suggested that the most reported variants among Chinese, Japanese, and Thai patients with CH have been identified in DUOX2 (12,13,15), suggesting that DUOX2 variants are an even more frequent causative factor for CH than previously recognized.…”

“…Variants in DUOX2 have been frequently reported, especially in East Asia (11)(12)(13)(14). Several studies have suggested that the most reported variants among Chinese, Japanese, and Thai patients with CH have been identified in DUOX2 (12,13,15), suggesting that DUOX2 variants are an even more frequent causative factor for CH than previously recognized. In particular, the p.Lys530* and p.Arg1110Gln variants have been reported in Asian populations, including Chinese (16)(17)(18), Japanese (19,20), Korean (21), and Malaysian ( 22) patients.…”

Mutational screening of the TPO and DUOX2 genes in Argentinian children with congenital hypothyroidism due to thyroid dyshormonogenesis.

“…p.Pro138Leu, p.Pro142Arg and p.Leu264Cysfs*57 are located in the peroxidase-like domain, whereas p.Gln899Serfs*21, p.Thr920Ile and p.Phe966Serfs*29 are present in the transmembrane domain. Only two variants were described previously associated with congenital hypothyroidism, the p.Pro138Leu [46, 47] and the p.Phe966Serfs*29 variant [6, 11,24,40,41,46,[48][49][50][51]. The frameshift p.Phe966Serfs*29, commonly reported as p.S965fsX994 is one of the most frequent mutations in DUOX2 gene.…”

Cost-minimization analysis of sequential genetic testing versus targeted next-generation sequencing gene panels in patients with pheochromocytoma and paraganglioma

“…Peripheral blood samples of the patients were prospectively collected. Genomic DNA was extracted in a manner similar to that described previously [17]. To identify the variants, clinical exome sequencing was performed using the Illumina MiSeq V R system (Illumina, San Diego, CA) with the TruSight One Sequencing Panel V R .…”