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

Wang, Huijuan; Kong, Xiaohong; Pei, Yanrui; Cui, Xuemei; Zhu, Yi; He, Zixuan; Wang, Yanxia; Zhang, Lirong; Zhuo, Lixia; Chen, Chao; Yan, Xiaoli

doi:10.3892/mmr.2020.11078

Cited by 17 publications

(12 citation statements)

References 47 publications

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“…DUOX2 is mainly involved in the production of peroxide protein complexes and catalyzes the synthesis of thyroid hormones in thyroid follicular cells (25). Studies have found that mutations in DUOX2 can initiate CH, but the clinical phenotype, primarily the manifestation of TCH, is variable (26,27). In this study, except for the mutations observed in patients P1, P10, and P12, all genes merged with one or two DUOX2 mutations.…”

Section: Discussionmentioning

confidence: 56%

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

Hao

Dong

et al. 2021

Front. Endocrinol.

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PurposeCongenital hypothyroidism (CH) is the most common neonatal endocrine disease; its early detection ensures successful treatment and prevents complications. However, its molecular etiology remains unclear.MethodsWe used second-generation sequencing to detect 28 pathogenic genes in 15 Chinese Han patients with CH in Shenzhen, China, and analyzed the genetic pattern of the pathogenic genes through their pedigrees. The pathogenicity assessment of gene mutations was performed based on the American College of Medical Genetics and Genomics (ACMG) classification guidelines, inheritance models, and published evidence.ResultsMutations in several target genes were identified in 14 of 15 patients (93.33%); these mutations were distributed in eight genes (DUOX2, DUOXA2, TPO, TG, TSHR, FOXE1, KDM6A, and POU1F1). DUOX2 exhibited the highest mutation frequency (44%, 11/25), followed by TPO (16%, 4/25) and TG (16%, 4/25). DUOX2 exhibited the highest biallelic mutation (7/15). Eight out of 25 variants verified by the ACMG guidelines were classified as pathogenic (P, category 1) or possibly pathogenic (LP, Type 2), namely six variants of DUOX2, and one variant of TPO and DUOXA2. Five new mutations were detected: one in DUOX2, which was located in the splicing region of mRNA (c.1575-1G>A), three new missense mutants, p.A291T, p.R169W, and p. S1237dup, and one new TPO missense variant c.2012G>T (p.W671L). The main criteria for determining the genotype–phenotype relationship were a diagnostic detection rate of 53.33% (8/15) and combination of three or more gene mutations.ConclusionsCH gene mutations in the population may be mainly manifested in genes influencing thyroid hormone synthesis, such as DUOX2 compound heterozygous mutations, which exhibited a high detection rate. The clinical manifestations are diverse, and mainly include transient CH. Therefore, genetic screening is recommended for CH patients to determine the correlation between clinical phenotypes and gene mutations, which will assist in clinical management.

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Section: Discussionmentioning

confidence: 56%

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

Hao

Dong

et al. 2021

Front. Endocrinol.

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“…However, the detection rate of variants in TD cases has been shown to be only approximately 5% (3,39). Unlike TD, DH appears to have a detectable genetic basis in many cases (40,41). Using WES, the variant detection rate was 69.0% in our cohort.…”

Section: Discussionmentioning

confidence: 65%

Genetic and Phenotypic Characteristics of Congenital Hypothyroidism in a Chinese Cohort

et al. 2021

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BackgroundThe molecular etiology and the genotype–phenotype correlation of congenital hypothyroidism (CH) remain unclear.MethodsWe performed genetic analysis in 42 newborns with CH using whole-exome sequencing. Patients were divided into a single-gene group and a multi-gene group according to the number of affected genes, or divided into a monoallelic group, a biallelic group, and an oligogenic group according to the pattern of the detected variants. The clinical characteristics were compared between groups.ResultsThyroid dysgenesis (TD) was observed in 10 patients and goiter in 5 patients, whereas 27 patients had normal-sized gland-in-situ (GIS). We identified 58 variants in five genes in 29 patients. The genes with the most frequent variants were DUOX2 (70.7%), followed by TSHR (12.1%), DUOXA2 (10.3%), and TPO (5.2%). Variants in the genes causing dyshormonogenesis (DH) were more common than those in the genes causing TD (87.9% versus 12.1%). Among the patients with detected variants, 26 (89.7%) were harboring a single gene variant (single-gene group), which include 22 patients harboring biallelic variants (biallelic group) and four patients harboring monoallelic variants (monoallelic group). Three (10.3%) patients harbored variants in two or three genes (multi-gene group or oligogenic group). Compared with the single-gene group, the levothyroxine (L-T4) dose at 1 year of age was higher in the multi-gene group (p = 0.018). A controllable reduction in the L-T4 dose was observed in 25% of patients in the monoallelic group and 59.1% of patients in the biallelic group; however, no patients with such reduction in the L-T4 dose were observed in the oligogenic group.ConclusionsPatients with normal-sized GIS accounted for the majority of our cohort. Genetic defects in the genes causing DH were more common than those in the genes causing TD, with biallelic variants in DUOX2 being dominant. DH might be the leading pathophysiology of CH in Chinese individuals.

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“…We reviewed the literatures and analyzed the various detection rate of T SHR variants among different populations in 23 studies, 10 , 14–35 the results are shown in Table 2 . The prevalence of variants among different populations was also analyzed.…”

Section: Resultsmentioning

confidence: 99%

Variant of TSHR is Not a Frequent Cause of Congenital Hypothyroidism in Chinese Han Patients

Xue

Yang

et al. 2021

IJGM

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Purpose To screen variants of the thyroid stimulating hormone receptor ( TSHR ) gene among congenital hypothyroidism (CH) patients. Patients and Methods We conducted a genetic screening of the TSHR gene in a cohort of 125 Chinese CH patients. Variants were detected by customized targeted next-generation sequencing. Results A total of 11 TSHR missense heterozygous variants were identified in 14 CH patients. Six variants were in the transmembrane domains, four variants were in the leucine-rich repeats and one variant was located in the hinge region of the TSHR protein. p.F525S was the most prevalent variant with an allele frequency of 0.016, followed by p.R450H with an allele frequency of 0.012. The allele frequency of most variants was higher in our cohort than those of other populations. Conclusion The prevalence of TSHR variants was 11.2%. Variant p.F525S was the most prevalent variant with an allele frequency of 0.016. The prevalence of TSHR variants was different from other populations.

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

Cited by 17 publications

References 47 publications

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

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

Genetic and Phenotypic Characteristics of Congenital Hypothyroidism in a Chinese Cohort

Variant of TSHR is Not a Frequent Cause of Congenital Hypothyroidism in Chinese Han Patients

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