The genetic characteristics of congenital hypothyroidism in China by comprehensive screening of 21 candidate genes

Sun, Feng; Zhang, Junxiu; Yang, Changyi; Gao, Guan-Qi; Zhu, Wenbin; Han, Bing; Zhang, Lele; Wan, Yue-Yue; Ye, Xiaoping; Ma, Yuru; Zhang, Manman; Liu, Yang; Zhang, Qian-Yue; Liu, Wei; Guo, Cuicui; Chen, Gang; Zhao, Shuang‐Xia; Song, Kun; Song, Hwangjun

doi:10.1530/eje-17-1017

Cited by 88 publications

(88 citation statements)

References 47 publications

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“…However, in the patient cohort, dH (n=32) was more common than Td (n=11). This result is in agreement with the data reported in china (27)(28)(29)(30)(31). Given that dH is largely caused by genetic Table Ⅱ.…”

Section: Discussionsupporting

confidence: 92%

“…However, phenotypic variability observed in patients with same mutations indicated the influence of other factors, such as genetic heterogeneity (15,34,42,43,(48)(49)(50). The present study found a high percentage (25.6%) of involvement of oligogenic mutations in studied cases, which is similar to that of previous studies simultaneously assessing multiple genes (15,(30)(31)(32). These studies reported frequent oligogenic involvement in cH, with oligogenic mutations in 20-43.5% of patients with cH and GiS and/or patients with Td in different ethnic populations.…”

Section: Minor Allele Frequencysupporting

confidence: 89%

“…Thus, those examined as athyreosis could not be excluded for the likelihood of ectopy. Similarly, other studies have found variants associated with dH in patients with athyreosis (30,32). in addition, 2 individual variants in genes associated with pituitary development or central cH (PROP1 and TRHR) respectively were found in 1 cH patient with GiS and 1 patient with Td, and both variants co-occurred with genetic variants associated with DH.…”

Section: Discussionsupporting

confidence: 56%

“…The general mutation profiles of patients with CH demonstrated by these studies were similar. For example, the total mutation rate in cH patients reported in these studies was relatively high, i.e., 48.5% (29), 65.09% (31), 80.9% (30) and 72% (the present study). DUOX2 mutations were the prevalent genetic alterations in these studies, with a mutation rate of 31.8% (29), 31.3% (31), 60% (30) and 44% (the present study).…”

Section: Minor Allele Frequencycontrasting

confidence: 38%

“…The data of the present study were compared with those of several similar studies that analyzed the mutation spectrum of cH patients in china by using nGS (29)(30)(31). The investigated patients in the present study were from northwestern china (Shaanxi Province), whereas those in the previous studies were mainly from southern china (Jiangsu and Guangxi Provinces).…”

Section: Minor Allele Frequencymentioning

confidence: 89%

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Mutation spectrum analysis of 29 causative genes in 43 Chinese patients with congenital hypothyroidism

et al. 2020

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congenital hypothyroidism (cH) is the most common neonatal endocrine disorder with a genetic origin. The purpose of the present study was to analyze the mutation spectrum of cH patients in china. a targeted next-generation sequencing panel covering all exons of 29 cH-related causative genes was used in 43 Han chinese patients with cH [11 dysgenesis and 32 glands in situ (GiS)]. The functional impact and pathogenicity of detected variants were analyzed using a comprehensive bioinformatics approach and co-segregation studies. a total of 47 rare non-polymorphic variants in 9 target genes associated with thyroid hormone synthesis (DUOX2, DUOXA2, TPO, TG, SLC26A4 and SLC5A5), thyroid stimulating hormone resistance (TSHR) and central hypothyroidism (PROP1 and TRHR) were identified in 31 patients (31/43, 72%). of these variants, 8 were novel, including 3 in DUOX2, 2 in TPO, 3 in TSHR and 1 in SLC5A5. Variants were mostly affected by DUOX2, TG, TPO and TSHR. approximately 44% of the patients (19/43) carried DUOX2 variants. The mutation detection rates in patients with GiS were higher compared with patients with dysgenesis [25/32 (78%) vs. 6/11 (54%)]. oligogenic mutations were detected in 25.6% of the total cases and 35% of the mutated cases. Genetic basis was ascertained in 13 patients, reaching a diagnosis detection rate of 30%. in conclusion, genetic defects in dyshormonogenesis, mainly in DUOX2, were the main genetic cause of cH in the chinese population. oligogenicity is highly involved in cH pathogenesis and may thus be an important factor in common phenotypic variability observed in patients with cH.

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Section: Discussionsupporting

confidence: 92%

Section: Minor Allele Frequencysupporting

confidence: 89%

Section: Discussionsupporting

confidence: 56%

Section: Minor Allele Frequencycontrasting

confidence: 38%

Section: Minor Allele Frequencymentioning

confidence: 89%

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Mutation spectrum analysis of 29 causative genes in 43 Chinese patients with congenital hypothyroidism

et al. 2020

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Nicotinamide nucleotide transhydrogenase mutation analysis in Chinese patients with thyroid dysgenesis

Tian

Wang

et al. 2021

American J of Med Genetics Pt A

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Thyroid dysgenesis (TD) accounts for 80% cases of congenital hypothyroidism, which is the most common neonatal disorder. Until now, the gene mutations have been reported associated with TD can only account for 5% cases, suggesting the genetic heterogeneity of the pathology. Nicotinamide nucleotide transhydrogenase (NNT) plays a crucial role in regulating redox homeostasis, patients carrying NNT mutations have been described with a clinical phenotype of hypothyroidism. As TD risk is increased in the context of several syndromes and redox homeostasis is vital for thyroid development and function, NNT might be a candidate gene involved in syndromic TD. Therefore, we performed target sequencing (TS) in 289 TD patients for causative mutations in NNT and conducted functional analysis of the gene mutations. TS and Sanger sequence were used to screen the novel mutations. For functional analysis, we performed western blot, measurement of NADPH/NADPtotal and H2O2 generation, cell proliferation, and wounding healing assay. As a result, three presumably pathogenic mutations (c.811G > A, p.Ala271Ser; c.2078G > A, p.Arg693His; and c.2581G > A, p.Val861Met) in NNT had been identified. Our results showed the damaging effect of NNT mutations on stability and catalytic activity of proteins and redox balance of cells. In conclusion, our findings provided novel insights into the role of the NNT isotype in thyroid physiopathology and broaden the spectrum of pathogenic genes associated with TD. However, the pathogenic mechanism of NNT in TD is still need to be investigated in further study.

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Maternal exposure to O3 and NO2 may increase the risk of newborn congenital hypothyroidism: a national data-based analysis in China

Shang

Yang

et al. 2021

Environ Sci Pollut Res

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Maternal exposure to air pollution during pregnancy is associated with adverse outcomes in the offspring, but limited studies focused on the impacts of gaseous air pollution on newborn congenital hypothyroidism (CH). Therefore, a national data-based analysis was conducted to explore the association between maternal exposure to gaseous air pollution and the incidence of CH in China. Annual average exposure levels of SO2, NO2, CO, and O3 from January 1, 2014, to December 30, 2014, were acquired from the Chinese Air Quality Online Monitoring and Analysis Platform. The annual incidence of newborn CH from October 1, 2014, to September 30, 2015, was collected from the Chinese Maternal and Child Health Surveillance Network. Temperature and toxic metal in wastewater in 2014 were also collected as covariates. Maternal exposure to O3 and NO2 in 1 μg/m3 level increment was positively associated with newborn CH, with an OR of 1.055 (95% CI 1.011, 1.102) and 1.097 (95% CI 1.019, 1.182) after adjusting for covariates completely. Compared with the lowest level of O3, maternal exposure to the 4th quartile of O3 was positively associated with newborn CH (OR 1.393, 95% CI 1.081, 1.794) after adjusting for covariates completely. And the 3rd and 4th quartiles of NO2 were associated positively with CH (OR 1.576, 95% CI 1.025, 2.424, and OR 1.553, 95% CI 0.999, 2.414, respectively) compared with the lowest level of NO2. By fitting the ROC curve, 93.688 μg/m3 in O3 might be used as cutoff to predict the incidence of newborn CH in China.

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The genetic characteristics of congenital hypothyroidism in China by comprehensive screening of 21 candidate genes

Cited by 88 publications

References 47 publications

Mutation spectrum analysis of 29 causative genes in 43 Chinese patients with congenital hypothyroidism

Mutation spectrum analysis of 29 causative genes in 43 Chinese patients with congenital hypothyroidism

Nicotinamide nucleotide transhydrogenase mutation analysis in Chinese patients with thyroid dysgenesis

Maternal exposure to O3 and NO2 may increase the risk of newborn congenital hypothyroidism: a national data-based analysis in China

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