The rs1991517 polymorphism is a genetic risk factor for congenital hypothyroidism.
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ABSTRACT:
SUBMITTER: Kollati Y
PROVIDER: S-EPMC7266893 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Congenital primary hypothyroidism (CH; OMIM 218700) is characterized by an impaired thyroid development, or dyshormonogenesis, and can lead to intellectual disability and growth retardation if untreated. Most of the children with congenital hypothyroidism present thyroid dysgenesis, a developmental anomaly of the thyroid. Various genes have been associated with thyroid dysgenesis, but all known genes together can only explain a small number of cases. To identify novel genetic causes for congenital hypothyroidism, we performed trio whole-exome sequencing in an affected newborn and his unaffected parents. A predicted damaging de novo missense mutation was identified in the ZBTB26 gene (Zinc Finger A and BTB Domain containing 26). An additional cohort screening of 156 individuals with congenital thyroid dysgenesis identified two additional ZBTB26 gene variants of unknown significance. To study the underlying disease mechanism, morpholino knock-down of zbtb26 in Xenopus laevis was carried out, which demonstrated significantly smaller thyroid anlagen in knock-down animals at tadpole stage. Marker genes expressed in thyroid tissue precursors also indicated a specific reduction in the Xenopus ortholog of human Paired-Box-Protein PAX8, a transcription factor required for thyroid development, which could be rescued by adding zbtb26. Pathway and network analysis indicated network links of ZBTB26 to PAX8 and other genes involved in thyroid genesis and function. GWAS associations of ZBTB26 were found with height. Together, our study added a novel genetic risk factor to the list of genes underlying congenital primary hypothyroidism and provides additional support that de novo mutations, together with inherited variants, might contribute to the genetic susceptibility to CH.
| S-EPMC8701029 | biostudies-literature
Project description: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.
| S-EPMC8446595 | biostudies-literature
Project description:Loss-of-function mutations in dual oxidase (DUOX) 2 are the most common genetic variants found in congenital hypothyroidism (CH), and similar mutations have been recently reported in few very-early-onset inflammatory bowel disease (IBD) patients without CH. If DUOX2 variants indeed increase susceptibility for IBD, the enrichment of DUOX2 mutation carriers among CH patients should be reflected in higher risk for developing IBD. Using a database containing health insurance claims data for over 230 million patients in the United States, 42,922 subjects with CH were identified based on strict inclusion criteria using diagnostic codes. For subgroup analysis, CH patients with pharmacy records were stratified as transient or permanent CH based on the absence or presence of levothyroxine treatment, respectively. Patients were matched to an equal-sized, age- and gender-matched non-CH group. Compared to controls, CH patients had a 73% higher overall IBD prevalence (0.52% vs 0.30%; P?<?0.0001). The CH-associated relative risk was higher for indeterminate or ulcerative colitis than Crohn's disease. Patients with transient CH had higher odds for IBD (OR 2.39 (95% CI 1.77-3.23) than those with permanent CH (1.69 (95% CI 1.31-2.18). We conclude that patients with CH are at an increased risk of developing IBD. The risk was highest for patients with transient CH, for which partial defects in the DUOX2 system are a particularly common finding.
| S-EPMC6033893 | biostudies-other
Project description:BackgroundA meta-analysis of polymorphism C677T (rs1801133) of the methylene tetrahydrofolate reductase (MTHFR) gene as a potential risk factor for congenital heart disease (CHD) in Chinese paediatric population was studied in view of the previously reported controversial results.MethodsWe searched literature including PubMed, Embase, Cochrane Library, CNKI, Wanfang, and VIP databases that resulted in the identification of a total of 21 separate studies with 6414 subjects that met the inclusion criteria in the Chinese population. The quality assessment of the included studies was preformed and relevant information was collected. We chose the fixed-effect model or random-effect model to calculate the pooled odds ratio (ORs) and its corresponding 95% confidence interval (95% CI) where appropriate. Begg test was used to measure publication bias and sensitivity analyses were done to ensure authenticity of the outcome.ResultsWe observed a significant association between MTHFR C677T polymorphism and CHD development in all the genetic models evaluated. The pooled ORs and 95% CIs in all genetic models indicated that children's MTHFR C677T polymorphism was significantly associated with CHD.ConclusionOur study results indicate that MTHFR gene 677T polymorphism is a genetic risk factor in the development of CHD in Chinese paediatric population.
| S-EPMC5466217 | biostudies-literature
Project description:OBJECTIVE: Congenital hypothyroidism is characterized by inadequate thyroid hormone production in newborn infants. Many infants with CH have co-occurring congenital malformations. This is an investigation on the frequency and types of congenital anomalies in infants with congenital hypothyroidism born from May 2006-2010 in Hamadan, west province of Iran. METHODS: The Iranian neonatal screening program for congenital hypothyroidism was initiated in May 2005. This prospective descriptive study was conducted in infants diagnosed with congenital hypothyroidism being followed up in Pediatric Endocrinology Clinic of Besat Hospital, a tertiary care centre in Hamadan. Cases included all infants with congenital hypothyroidism diagnosed through newborn screening program or detected clinically. Anomalies were identified by clinical examination, echocardiography, and X-ray of the hip during the infant's first year of life. RESULTS: A total of 150 infants with biochemically confirmed primary congenital hypothyroidism (72 females and 78 males) were recruited during the period between May 2006-2010. Overall, 30 (20%) infants had associated congenital anomalies. The most common type of anomaly was Down syndrome. Seven infants (3.1%) had congenital cardiac anomalies such as: ASD (n=3), VSD (n=2), PS (n =1), PDA (n=1). Three children (2.6%) had developmental dysplasia of the hip (n=3). CONCLUSION: The overall frequency of Down syndrome, cardiac malformation and other birth defect was high in infants with CH. This reinforces the need to examine all infants with congenital hypothyroidism for the presence of associated congenital anomalies.
| S-EPMC3472568 | biostudies-other
Project description:Congenital hypothyroidism (CH) is the most frequent endocrine disorder in neonates. While several genetic mutations have been identified that result in developmental defects of the thyroid gland or thyroid hormone synthesis, genetic factors have yet to be identified in many CH patients along with the mechanisms underlying their pathophysiology. Mutations in the gene encoding the Krüppel-like transcription factor, GLI-similar 3 (GLIS3) have been associated with the development of a syndrome characterized by congenital hypothyroidism and neonatal diabetes and similar phenotypes were observed in mouse knockout models of Glis3. Patients with GLIS3-mediated CH exhibit diminished serum levels of thyroxine (T4) and triiodothyronine (T3) and elevated thyroid stimulating hormone (TSH) and thyroglobulin (TG). However, the inconsistent presentation of clinical features associated with this CH has made it difficult to ascertain a causative mechanism. Future elucidation of the biological functions of GLIS3 in the thyroid will be crucial to the discovery of new therapeutic opportunities for the treatment of CH.
| S-EPMC4131692 | biostudies-literature
Project description:BACKGROUND:Congenital hypothyroidism (CH) is one of the most common endocrine diseases in childhood. A significant proportion of CH cases are transient, but the risk factors for permanent CH (PCH) are not yet well established. The current guidelines suggest using levothyroxine until the age of 3?years, but some studies suggest the possibility of earlier discontinuation. However, few, if any, studies have followed up on the results of early discontinuation. This study aimed to identify predictive factors of transient CH among infants with CH. We also investigated the results in patients who underwent a trial of early discontinuation. METHODS:We gathered data regarding infants diagnosed with CH between July 2005 and July 2015 by retrospective chart review. Those with aplastic, hypoplastic or ectopic glands on thyroid ultrasonography or scan were excluded. Among them, early discontinuation subgroup was defined as those who discontinued levothyroxine before 30?months of age. RESULTS:From the 80 infants (40 males, 40 females) enrolled in this study, 51 were preterm. Nine (11.3%) were diagnosed with PCH. Compared with transient cases, those with PCH were on higher levothyroxine dose at discontinuation (4.3 vs 2.9??g/kg, P?<?0.001). There was no difference in the proportion of permanent cases between preterm and full-term groups. In preterm group,infants with PCH required higher levothyroxine dose at discontinuation than those with transient CH (3.8 vs 2.5??g/kg, P?=?0.018). Levothyroxine discontinuation at a dose of 2.86??g/kg could suggest PCH (sensitivity, 88.9%; specificity, 71.0%). Among the 9 patients who underwent a trial of early discontinuation, 8 successfully discontinued levothyroxine. CONCLUSION:The majority of CH patients discontinued levothyroxine successfully, including those who underwent a trial of early discontinuation. Higher levothyroxine dose at the time of discontinuation was found to be a predictive factor for PCH.
| S-EPMC6873549 | biostudies-literature
Project description:BackgroundCongenital cytomegalovirus immunopathogenesis is largely unknown and multifactorial due to the complex interactions between viral, maternal, placental, and child factors. Polymorphisms in the HLA-E binding UL4015-23 peptide mimics HLA-E complexed peptides from certain HLA-A, -B, -C and -G alleles, which regulate the cellular immune response driven by natural killer-cells (NK) and CD8 + T cells. The aim of this study was to compare UL4015-23 peptides distribution in congenital CMV and the counterpart HLA Class I peptides in a healthy cohort to investigate risk factors and markers for cCMV disease. In this 10-year retrospective study, the UL40 gene was directly sequenced from 242 clinical samples from 199 cases of congenital CMV (166 children and 33 pregnant or breast feeding women). Distribution of HLA-E binding UL4015-23 peptides was analyzed and compared to those of HLA Class I observed in a cohort of 444 healthy individuals.ResultsNineteen different HLA-E binding UL4015-23 peptides were found. Three of them (VMAPRTLIL, VMAPRTLLL, VMAPRTLVL) were found in 88.3% of UL40 and 100% of HLA Class I of healthy individuals. In contrast, 15 of them (10.7%) were not found in HLA Class I. The VMAPRTLFL peptide was found in 1% of UL40 and all HLA-G alleles. Significant differences in peptide (VMAPRTLIL, VMAPRTLLL, VMAPRTLVL, other UL4015-23 peptides, other HLA Class I peptides) distribution between UL4015-23 from congenital CMV and HLA-A, -B, -C and -G from healthy individuals were found.ConclusionsOur findings suggest that a mismatch between UL4015-23 peptides and HLA Class I peptides between children and mothers might play a role in congenital CMV disease, and it may account for differences in outcome, morbidity and sequelae.
| S-EPMC9208114 | biostudies-literature
Project description:Congenital hypothyroidism (CH) is the most common neonatal endocrine disorder and one of the most common preventable causes of intellectual disability in the world. CH may be due to developmental or functional thyroid defects (primary or peripheral CH) or be hypothalamic-pituitary in origin (central CH). In most cases, primary CH is caused by a developmental malformation of the gland (thyroid dysgenesis, TD) or by a defect in thyroid hormones synthesis (dyshormonogenesis, DH). TD represents about 65% of CH and a genetic cause is currently identified in fewer than 5% of patients. The remaining 35% are cases of DH and are explained with certainty at the molecular level in more than 50% of cases. The etiology of CH is mostly unknown and may include contributions from individual and environmental factors. In recent years, the detailed phenotypic description of patients, high-throughput sequencing technologies, and the use of animal models have made it possible to discover new genes involved in the development or function of the thyroid gland. This paper reviews all the genetic causes of CH. The modes by which CH is transmitted will also be discussed, including a new oligogenic model. CH is no longer simply a dominant disease for cases of CH due to TD and recessive for cases of CH due to DH, but a far more complex disorder.
| S-EPMC9218988 | biostudies-literature
Project description:Neonatal screening for congenital primary hypothyroidism (CH) is mandatory in Germany but medical care thereafter remains inconsistent. Therefore, the registry HypoDok of the German Society of Pediatric Endocrinology and Diabetology (DGKED) was analyzed to evaluate the implementation of evidence-based guidelines and to assess the number of included patients. Inclusion criteria were (i) date of birth between 10/2001 and 05/2020 and (ii) increased thyroid-stimulating hormone (TSH) at screening and/or confirmation. The cohort was divided into before (A) and after (B) guideline publication in 02/2011, to assess the guideline's influence on medical care. A total of 659 patients were analyzed as group A (n = 327) and group B (n = 332) representing 17.5% and 10.3% of CH patients identified in the German and Austrian neonatal screening program during the respective time period. Treatment start and thyroxine doses were similar in both groups and consistent with recommendations. Regular follow-ups were documented. In the first three years of life, less than half of the patients underwent audiometry; developmental assessment was performed in 49.3% (A) and 24.8% (B) (p < 0.01). Documentation of CH patient care by pediatric endocrinologists seemed to be established, however, it reflected only a minority of the affected patients. Therefore, comprehensive documentation as an important instrument of quality assurance and evidence-based medicine should be legally enforced and officially funded in order to record, comprehend, and optimize care and outcome in patients with rare diseases such as CH.
| S-EPMC8006240 | biostudies-literature