The mutation screening in candidate genes related to thyroid dysgenesis by targeted next‐generation sequencing panel in the Chinese congenital hypothyroidism

2021 ◽  
Author(s):  
Rui‐Jia Zhang ◽  
Guang‐lin Yang ◽  
Feng Cheng ◽  
Feng Sun ◽  
Ya Fang ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Candidate Genes ◽  
Congenital Hypothyroidism ◽  
Mutation Screening ◽  
Next Generation ◽  
Thyroid Dysgenesis ◽  
Targeted Next Generation Sequencing ◽  
Generation Sequencing

Targeted next-generation sequencing (NGS) of nine candidate genes with custom AmpliSeq in patients and a cardiomyopathy risk group

2015 ◽  
Vol 446 ◽  
pp. 132-140 ◽  
Author(s):  
Andrey S. Glotov ◽  
Sergey V. Kazakov ◽  
Elena A. Zhukova ◽  
Anton V. Alexandrov ◽  
Oleg S. Glotov ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Candidate Genes ◽  
Risk Group ◽  
Next Generation ◽  
Targeted Next Generation Sequencing ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Targeted Next-Generation Sequencing for Congenital Hypothyroidism With Positive Neonatal TSH Screening

2020 ◽  
Vol 105 (8) ◽  
pp. e2825-e2833 ◽  
Author(s):  
Takeshi Yamaguchi ◽  
Akie Nakamura ◽  
Kanako Nakayama ◽  
Nozomi Hishimura ◽  
Shuntaro Morikawa ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Congenital Hypothyroidism ◽  
Gene Dosage ◽  
Next Generation ◽  
Gene Dosage Effect ◽  
Targeted Next Generation Sequencing ◽  
Pathogenic Variants ◽  
Published Evidence ◽  
Unknown Significance ◽  
Generation Sequencing

Abstract Purpose Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder; however, its molecular etiology remains poorly understood. Methods We performed genetic analysis of 24 causative genes using next-generation sequencing in 167 CH cases, comprising 57 dyshormonogenesis (DH), 32 dysgenesis (TD) and 78 undiagnosed. The pathogenicity of variants was assessed by the American College of Medical Genetics guidelines, inheritance pattern, and published evidence. Furthermore, we compared the oligogenic groups and monogenic groups to examine the correlation between variant dosage and severity. Results We identified variants in 66.5% cases (111/167) and 15 genes, DUOX2, TSHR, PAX8, TG, TPO, DUOXA2, JAG1, GLIS3, DUOX1, IYD, SLC26A4, SLC5A5, SECISBP2, DIO1, and DIO3. Biallelic variants were identified in 12.6% (21/167), oligogenic in 18.0% (30/167), and monogenic in 35.9% (60/167); however, 68.5% of variants were classified as variant of unknown significance (VUS). Further examinations showed that 3 out of 32 cases with TD (9.4%) had pathogenic variants (2 of TSHR and 1 of TPO), and 8 out of 57 cases with DH (14.0%) (7 of DUOX2, 1 of TG) had pathogenic variants. In addition, TSH levels at the first visit were significantly higher in the oligogenic group than in the monogenic group. Conclusions The detection rate of pathogenic variants in Japanese CH was similar to that previously reported. Moreover, oligogenic cases were likely to be more severe than monogenic cases, suggesting that CH may exhibit a gene dosage effect. Further analysis of VUS pathogenicity is required to clarify the molecular basis of CH.

scholarly journals High Diagnostic Yield of Targeted Next-Generation Sequencing in a Cohort of Patients With Congenital Hypothyroidism Due to Dyshormonogenesis

2021 ◽  
Vol 11 ◽  
Author(s):  
Athanasia Stoupa ◽  
Ghada Al Hage Chehade ◽  
Rim Chaabane ◽  
Dulanjalee Kariyawasam ◽  
Gabor Szinnai ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Congenital Hypothyroidism ◽  
Diagnostic Yield ◽  
Genetic Defect ◽  
Genetic Diagnosis ◽  
Compound Heterozygous ◽  
Next Generation ◽  
Hormone Production ◽  
Targeted Next Generation Sequencing ◽  
Generation Sequencing

ObjectiveTo elucidate the molecular cause in a well-characterized cohort of patients with Congenital Hypothyroidism (CH) and Dyshormonogenesis (DH) by using targeted next-generation sequencing (TNGS).Study designWe studied 19 well-characterized patients diagnosed with CH and DH by targeted NGS including genes involved in thyroid hormone production. The pathogenicity of novel mutations was assessed based on in silico prediction tool results, functional studies when possible, variant location in important protein domains, and a review of the recent literature.ResultsTNGS with variant prioritization and detailed assessment identified likely disease-causing mutations in 10 patients (53%). Monogenic defects most often involved TG, followed by DUOXA2, DUOX2, and NIS and were usually homozygous or compound heterozygous. Our review shows the importance of the detailed phenotypic description of patients and accurate analysis of variants to provide a molecular diagnosis.ConclusionsIn a clinically well-characterized cohort, TNGS had a diagnostic yield of 53%, in accordance with previous studies using a similar strategy. TG mutations were the most common genetic defect. TNGS identified gene mutations causing DH, thereby providing a rapid and cost-effective genetic diagnosis in patients with CH due to DH.

GERMLINE GCM2 MUTATION SCREENING IN CHINESE PRIMARY HYPERPARATHYROIDISM PATIENTS

2020 ◽  
Vol 26 (10) ◽  
pp. 1093-1104
Author(s):  
An Song ◽  
Yi Yang ◽  
Yabing Wang ◽  
Shuzhong Liu ◽  
Min Nie ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Primary Hyperparathyroidism ◽  
Glial Cell ◽  
Rare Variants ◽  
Mutation Screening ◽  
Next Generation ◽  
College Hospital ◽  
Targeted Next Generation Sequencing ◽  
Asian Populations ◽  
Generation Sequencing

Objective: Glial cell missing 2 (GCM2), the critical regulator in the development of parathyroid glands, has been associated with the pathogenesis of primary hyperparathyroidism (PHPT). Relevant data in Chinese and other Asian populations are still lacking. This study aimed to screen the germline mutations of GCM2 in Chinese PHPT patients. Methods: A total of 232 patients diagnosed with PHPT at the Peking Union Medical College Hospital from July, 2016, to February, 2019, were screened using targeted next-generation sequencing to identify rare variants of 8 candidate genes associated with PHPT, including GCM2. Luciferase assays were performed to determine the functional impact of the GCM2 variants. Results: Four male patients were found to carry 3 rare missense variants of the GCM2 gene, including c.1162A>G (p.K388E), c.1144G>A (p.V382M), and c.1247A>G (p.Y416C). Two variants (p.K388E and p.V382M) located within a highly conserved region were associated with GCM2 transactivation function. The 2 cases carrying the p.K388E mutation had a pathology of carcinoma, and the case with the p.V382M mutation had atypical adenoma. Conclusion: This study determined an overall GCM2 gain-of-function mutation frequency of 1.3% in a relatively large-sample-sized Chinese PHPT cohort and supported a higher malignant tendency in cases carrying activating GCM2 mutations. Hence, preoperative screening for these GCM2 mutations might be beneficial to treatment decisions, and longer follow-up for such patients is recommended. Abbreviations: aa = amino acid; CASR = calcium-sensing receptor; CCID = C-terminal conserved inhibitory domain; CDC73 = cell division cycle 73; DBD = DNA-binding domain; DNA = deoxyribonucleic acid; FIHP = familial isolated hyperparathyroidism; GCM2 = glial cell missing 2; GBS = GCM-binding site; MEN1 = multiple endocrine neoplasia type 1; NGS = next-generation sequencing; PA = parathyroid adenoma; PCR = polymerase chain reaction; PHPT = primary hyperparathyroidism; PTH = parathyroid hormone; SNV = single nucleotide variant; VUS = variants of uncertain clinical significance

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