Clinical spectrum and molecular basis in 19 Chinese patients with 46, XY disorder of sexual development caused by NR5A1 mutations.

Background: Nuclear receptor subfamily 5 group A member 1 (NR5A1) plays pivotal roles in steroidogenesis and gonadal development. 46, XY disorder of sexual development (DSD) caused by NR5A1 mutations is a rare genetic condition. This study aimed to provide a comprehensive analysis of the clinical characteristics and molecular defects observed in 19 Chinese patients with NR5A1 variants, including assessing the deleterious effects of novel variants in vitro and evaluating their functional impact on the gonad and adrenal glands in vivo.

is needed for the proliferation and maturation of thyroid follicle cells via Notch signaling.

Thyroid dysgenesis (TD) is the common pathogenic mechanism of congenital hypothyroidism (CH). In addition, known pathogenic genes are limited to those that are directly involved in thyroid development. To identify additional candidate pathogenetic genes, we performed forward genetic screening for TD in zebrafish, followed by positional cloning.

Identification of Eukaryotic Translation Initiation Factor 4B as a Novel Candidate Gene for Congenital Hypothyroidism.

Context: Congenital hypothyroidism (CH) is the most common endocrine disorder in neonates, but its etiology is still poorly understood.

Objective: We performed whole exome sequencing to identify a novel causative gene for CH and functional studies to validate its role in the occurrence of CH.

Methods: Whole exome sequencing in 98 CH patients not harboring known CH candidate genes and bioinformatic analysis were performed.

Deficiency of the HGF/Met pathway leads to thyroid dysgenesis by impeding late thyroid expansion.

The mechanisms of bifurcation, a key step in thyroid development, are largely unknown. Here we find three zebrafish lines from a forward genetic screening with similar thyroid dysgenesis phenotypes and identify a stop-gain mutation in hgfa and two missense mutations in met by positional cloning from these zebrafish lines. The elongation of the thyroid primordium along the pharyngeal midline was dramatically disrupted in these zebrafish lines carrying a mutation in hgfa or met.

Variant Screening and Phenotype Analysis in 367 Chinese Patients With Congenital Hypothyroidism.

Background: Genetic defects in the human thyroid-stimulating hormone (TSH) receptor () gene can cause congenital hypothyroidism (CH). However, the biological functions and comprehensive genotype-phenotype relationships for most variants associated with CH remain unexplored. We aimed to identify variants in Chinese patients with CH, analyze the functions of the variants, and explore the relationships between genotypes and clinical phenotypes.

Contactin 6, A Novel Causative Gene for Congenital Hypothyroidism, Mediates Thyroid Hormone Biosynthesis Through Notch Signaling.

Congenital hypothyroidism (CH) is the most common neonatal metabolic disorder. In patients with CH in China, thyroid dyshormonogenesis is more common than thyroid dysgenesis; however, the genetic causes of CH due to thyroid dyshormonogenesis remain largely unknown. Therefore, we aimed at identifying novel candidate causative genes for CH.

Genetic Screening and Functional Analysis of Thyroid Peroxidase Variants in Chinese Patients with Congenital Hypothyroidism.

Introduction: Congenital hypothyroidism (CH), the most common neonatal endocrine disorder worldwide, can be caused by variants in the thyroid peroxidase (TPO) gene. This study aimed to identify TPO variants in Chinese patients with CH, analyze their impact on TPO function, and establish relationships between TPO genotypes and clinical characteristics.

Methods: A total of 328 patients with CH were screened for TPO variants by performing whole-exome sequencing.

Identification of promoting better prognosis in papillary thyroid carcinoma along with Hashimoto's thyroiditis through WGCNA analysis.

Background: Hashimoto's thyroiditis (HT) is an autoimmune thyroid disease. Papillary thyroid carcinoma (PTC) is the most common endocrine cancer. In recent years the rate of coexistence between PTC and HT has increased but the relationship between them remains unclear, meaning it is necessary to find potential biomarkers for PTC coexistence with HT to predict its potential pathways.

Pathogenic variations in and contribute to congenital hypothyroidism due to dyshormonogenesis by regulating the Notch signalling pathway.

Background: In several countries, thyroid dyshormonogenesis is more common than thyroid dysgenesis in patients with congenital hypothyroidism (CH). However, known pathogenic genes are limited to those directly involved in hormone biosynthesis. The aetiology and pathogenesis of thyroid dyshormonogenesis remain unknown in many patients.

The transcription factor regulates pituitary development in zebrafish.

Background: ISL LIM homeobox 2, also known as insulin gene enhancer protein ISL-2 (), is a transcription factor gene that participates in a wide range of developmental events. However, the role of in the hypothalamus-pituitary-thyroid axis is largely unknown. In the present study, we characterized the expression patterns of and revealed its regulative role during embryogenesis using zebrafish.

In-frame deletion of SMC5 related with the phenotype of primordial dwarfism, chromosomal instability and insulin resistance.

Background: SMC5/6 complex plays a vital role in maintaining genome stability, yet the relationship with human diseases has not been described.

Methods: SMC5 variation was identified through whole-exome sequencing (WES) and verified by Sanger sequencing. Immunoprecipitation, cytogenetic analysis, fluorescence activated cell sorting (FACS) and electron microscopy were used to elucidate the cellular consequences of patient's cells.

Insights into the pathogenesis of hereditary angioedema using genetic sequencing and recombinant protein expression analyses.

Background: The pathogenesis of hereditary angioedema (HAE) type I and type II is linked to defective C1 esterase inhibitor (C1-INH) encoded by the SERPING1 gene. There are substantial variabilities in the clinical presentations of patients with HAE that are not directly correlated to the serum levels of C1-INH. The impact of SERPING1 variants on C1-INH expression, structure, and function is incompletely understood.

Large-scale forward genetic screening of zebrafish affecting thyroid development.

The thyroid follicular cells originate from the foregut endoderm and elucidating which genes and signaling pathways regulate their development is crucial for understanding developmental disorders as well as diseases in adulthood. We exploited unique advantages of the zebrafish model to carry an ENU-based forward mutagenesis screen aiming at identifying genes involved in the development and function of the thyroid follicular cells. ENU is an excellent chemical mutagen due to its high mutation efficiency and an indiscriminate selection of genes.

Lessons from 17β-HSD3 deficiency: Clinical spectrum and complex molecular basis in Chinese patients.

17β-Hydroxysteroid dehydrogenase type 3 (17β-HSD3) deficiency is rarely reported in Chinese patients with 46, XY disorders of sexual development (DSD). Seven subjects with 17β-HSD3 deficiency were identified from 206 Chinese 46, XY DSD patients using targeted next-generation sequencing (NGS). Serum AD and T levels were measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS).

PARD3 gene variation as candidate cause of nonsyndromic cleft palate only.

Nonsyndromic cleft palate only (NSCP) is a common congenital malformation worldwide. In this study, we report a three-generation pedigree with NSCP following the autosomal-dominant pattern. Whole-exome sequencing and Sanger sequencing revealed that only the frameshift variant c.

Tpo knockout in zebrafish partially recapitulates clinical manifestations of congenital hypothyroidism and reveals the involvement of TH in proper development of glucose homeostasis.

Congenital hypothyroidism (CH) is a highly prevalent but treatable neonatal endocrine disorder. Thyroid peroxidase (TPO) catalyzes key reactions in thyroid hormone (TH) synthesis. TPO mutations have been found to underlie approximately 5% of congenital hypothyroidism in Chinese patients with more severe phenotypes, the treatment of whom usually requires a higher dose of L-thyroxine.

Lymphocyte infiltration and thyrocyte destruction are driven by stromal and immune cell components in Hashimoto's thyroiditis.

Hashimoto's thyroiditis (HT) is the most common autoimmune disease characterized by lymphocytic infiltration and thyrocyte destruction. Dissection of the interaction between the thyroidal stromal microenvironment and the infiltrating immune cells might lead to a better understanding of HT pathogenesis. Here we show, using single-cell RNA-sequencing, that three thyroidal stromal cell subsets, ACKR1 endothelial cells and CCL21 myofibroblasts and CCL21 fibroblasts, contribute to the thyroidal tissue microenvironment in HT.

Phenotypic Heterogeneity and Fertility Potential of Patients With 17-Hydroxylase/17,20-lyase Deficiency.

Context: 17α-Hydroxylase/17,20-lyase deficiency (17OHD) is caused by a human CYP17A1 gene mutation and has the classical phenotype of hypertension, hypokalemia, sexual infantilism, and primary amenorrhea in females (46,XX) and disorders of sexual development in males (46,XY). To date, few cases of 17OHD have been reported, and the likelihood of pregnancy has rarely been explored.

Objective: To study the clinical characteristics, phenotype heterogeneity, genotyping, and the likelihood of pregnancy of patients with 17OHD.

The effect of radioiodine treatment on the characteristics of TRAb in Graves' disease.

Background: Graves' disease (GD) is one of the most common autoimmune thyroid diseases (AITDs) in humans, and thyrotropin receptor antibody (TRAb) is a characterized autoantibody in GD. The use of radioactive iodine therapy (RAI) for GD treatment is increasing.

Objectives: We studied the biological properties of TRAb and evaluated the effect of RAI therapy on TRAb in GD patients.

Generation of two induced pluripotent stem cell lines, SHIPMi001-A from a patient with hypertrophic cardiomyopathy caused by MYBPC3 gene mutation and SHIPMi002-A from a healthy male individual.

Hypertrophic cardiomyopathy is a hereditary disease with high incidence of sudden death and heart failure. Myosin-binding protein C3 (MYBPC3) is the most commonly mutation gene. Here, we report the establishment of two human induced pluripotent stem cell (iPSC) lines: one from a patient carrying a heterozygous c.

Correlation of DUOX2 residual enzymatic activity with phenotype in congenital hypothyroidism caused by biallelic DUOX2 defects.

DUOX2 is the most frequently mutated gene in patients with congenital hypothyroidism (CH) in China. However, no reliable genotype-phenotype relationship has been found in patients with DUOX2 mutations. In this study, DUOX2 mutations were screened in 266 CH patients, and the enzymatic activity of 89 DUOX2 variants was determined in vitro.

Mutation Screening and Functional Study of in Chinese Patients with Congenital Hypothyroidism.

Objective: Defects in the human solute carrier family 26 member 4 () gene are reported to be one of the causes of congenital hypothyroidism (CH). We aimed to identify mutations in Chinese patients with CH and analyze the function of the mutations.

Methods: Patients with primary CH were screened for 21 CH candidate genes mutations by targeted next-generation sequencing.