Newborn Screening and Molecular Profile of Congenital Hypothyroidism in a Chinese Population.
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ABSTRACT:
SUBMITTER: Yu B
PROVIDER: S-EPMC6216286 | biostudies-literature | 2018
REPOSITORIES: biostudies-literature
Publications
Newborn Screening and Molecular Profile of Congenital Hypothyroidism in a Chinese Population.
Yu Bin B Long Wei W Yang Yuqi Y Wang Ying Y Jiang Lihua L Cai Zhengmao Z Wang Huaiyan H
Frontiers in genetics 20181029
To review the characteristics of newborn screening of congenital hypothyroidism (CH), we reviewed the newborn screening data, including the levels of blood spot thyroid-stimulating hormone (TSH), and serum TSH and free thyroxine (FT4), of all newborn infants who accepted the newborn screening program during the last 14 years. In total, 437,342 newborn infants underwent CH screening and 192 infants were diagnosed with CH and the incidence of CH was 1:2278. The positive rate of the initial screeni ...[more]
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Project description:Context:Active surveillance of primary congenital hypothyroidism (CH) in a multiethnic population with established newborn bloodspot screening. Objective:To estimate performance of newborn screening for CH at different test thresholds and calculate incidence of primary CH. Design:Prospective surveillance from June 2011 to June 2012 with 3-year follow-up of outcomes. Relative likelihood ratios (rLRs) estimated to compare bloodspot TSH test thresholds of 6 mU/L and 8 mU/L, with the nationally recommended standard of 10 mU/L for a presumptive positive result. Setting:UK National Health Service. Patients:Clinician notification of children aged <5 years investigated following clinical presentation or presumptive positive screening result. Main Outcome Measure(s):Permanent primary CH status determined by clinician report of continuing T4 requirement at 3-year follow-up. Results:A total of 629 newborns (58.3% girls; 58.7% white ethnicity) were investigated following presumptive positive screening result and 21 children (52.4% girls; 52.4% white) after clinical presentation; 432 remained on treatment at 3-year follow-up. Permanent CH incidence was 5.3 (95% CI, 4.8 to 5.8) per 10,000 infants. With use of locally applied thresholds, sensitivity, specificity, and positive predictive value were 96.76%, 99.97%, and 66.88%, respectively. Compared with a TSH threshold of 10 mU/L, positive rLRs for 8 mU/L and 6 mU/L were 1.20 (95% CI, 0.82 to 1.75) and 0.52 (95% CI, 0.38 to 0.72), and negative rLRs were 0.11 (95% CI, 0.03 to 0.36) and 0.11 (95% CI, 0.06 to 0.20), respectively. Conclusions:Screening program performance is good, but a TSH threshold of 8 mU/L appears superior to the current national standard (10 mU/L) and requires further evaluation. Further research should explore the implications of transient CH for screening policy.
| S-EPMC6179177 | biostudies-other
Project description:BACKGROUND: Many of the countries in the Asia Pacific Region are just initiating newborn screening programs for selected metabolic and other congenital disorders. The present study is aimed at evaluating the congenital hypothyroidism screening program in the Southern region of Sri Lanka in terms of coverage, effectiveness of detecting and managing the cases. METHODS: The Newborn Screening System Database of Sri Lanka was reviewed from January 2011 to December 2012. The data of 47 babies who tested positive for hypothyroidism were analyzed. RESULTS: Total of 78,167 babies (99.0% of live births) were screened. Of them, 5.8% (n =?4,472) were discharged within 12 hrs of delivery where as 58.1% (n =?44969) were discharged afterwards but within next 12 hrs (i.e., day 1). The positive predictive value for congenital hypothyroidism (CH) was 9.0%. The incidences of primary CH among screened infants were 1:1682. False positive rate among screened infants was maintained below 0.70%. Mean age of serum confirmation was 23.8 (±8) days. CONCLUSIONS: In the light of the present findings, we would suggest direct communication systems, linking newborn screening program to the family unit. This would enhance timely follow-up for screen-positive infants and facilitate information sharing. Establishing a program with, public-private sector partnership should be considered. Costs could be contained if the specimen collection, its transportation and communication are carried out by this partnership and the laboratory tests are conducted by a non-profit organization such as a University in order to achieve the goal of universal coverage.
| S-EPMC4167276 | biostudies-literature
Project description:IntroductionNewborn screening (NBS) for congenital hypothyroidism (CH) in the Netherlands consists of thyroxine (T4), thyroid-stimulating hormone (TSH), and T4-binding globulin (TBG) measurements to detect thyroidal CH and central CH (CH-C). CH-C is detected by T4 or a calculated T4/TBG ratio, which serves as an indirect measure of free T4. TSH and TBG are only measured in the lowest 20 and 5% of daily T4 values, respectively. A recent evaluation of the Dutch NBS for CH showed that the T4 and T4/TBG ratio contribute to the detection of CH-C but also lead to a low positive predictive value (PPV). Dried blood spot (DBS) reference intervals (RIs) are currently unknown and may contribute to improvement of our NBS algorithm.Materials and methodsRIs of T4, TSH, TBG, and the T4/TBG ratio were determined according to Clinical & Laboratory Standards Institute guidelines in heel puncture cards from routine NBS in both sexes and at the common NBS sampling ages. Scatter plots were used to compare the healthy reference population to previously published data of CH-C patients and false positives.ResultsAnalyses of 1,670 heel puncture cards showed small differences between subgroups and led to the formulation of total sample DBS RIs for T4 (56-118 nmol/L), TSH (<2.6 mIU/L), TBG (116-271 nmol/L), and the T4/TBG ratio (>20). 46% of false-positive referrals based on T4 alone had a TBG below the RI, indicating preventable referral due to partial TBG deficiency. One case of CH-C also had partial TBG deficiency (TBG 59 and T4 12 nmol/L blood).Discussion/conclusionEstablished DBS RIs provided possibilities to improve the PPV of the Dutch CH NBS algorithm. We conclude that by taking partial TBG deficiency into account, approximately half of T4 false-positive referrals may be prevented while maintaining NBS sensitivity at the current level.
| S-EPMC8215938 | biostudies-literature
Project description:OBJECTIVES:Defects in the human thyroid peroxidase (TPO) gene are reported to be one of the causes of congenital hypothyroidism (CH) due to dyshormonogenesis. The aim of this study was to examine the TPO mutation spectrum and prevalence among patients with CH in the Guangxi Zhuang Autonomous Region of China and to define the relationships between TPO genotypes and clinical phenotypes. METHODS:Blood samples were collected from 192 patients with CH in the Guangxi Zhuang Autonomous Region, China and genomic DNA was extracted from peripheral blood leucocytes. All exons of the 10 common CH-associated genes including TPO together with their exon-intron boundaries were screened by next-generation sequencing (NGS). The effect of the novel TPO mutation was investigated by 'in silico' studies. RESULTS:NGS analysis of TPO in 192 patients with CH revealed 3 different variations in 2 individuals (2/192, 1%). Sequencing other CH candidate genes in the patients with TPO variants revealed that patient 1 was homozygous for c.2422delT TPO mutation combined with double heterozygous DUOX2 pathogenic variants (p.R683L/p.L1343F) and patient 2 was triallelic for TPO pathogenic variants (p.R648Q/p.T561M/p.T561M). The present study identified a novel TPO variation c.1682C>T/p.T561M; and four known mutations: c.2422delT/p.C808Afs×24 and c.1943C>T/p.R648Q in TPO, c.2048G>T/p.R683L and c.4027C>T/p.L1343F in DUOX2. CONCLUSIONS:Our study indicated that the prevalence of TPO mutations was 1% among studied Chinese patients with CH. More than two variations in one or more CH-associated genes can be found in a single patient, and may, in combination, affect the phenotype of the individual. A novel TPO variation c.1682C>T/p.T561M was found, thereby expanding the mutational spectrum of the gene.
| S-EPMC4874165 | biostudies-literature
Project description:Based on mutations in PAX8 is associated with thyroid dysgenesis. We aim to identify and characterize PAX8 mutations in a large cohort of congenital hypothyroidism(CH) from thyroid dysgenesis in Chinese population.We screened 453 unrelated Chinese patients with CH from thyroid dysgenesis for PAX8 mutations by sequencing the whole coding regions of PAX8 on genomic DNA isolated from blood. Cell transfection assays using various vector constructs and induced mutagenesis as well as electrophoretic mobility shift assays were used to investigate the effects of selected mutations on the transcribing and binding activities of PAX8 at the promoters of target genes for thyroglobulin (TG) and thyroperoxidase (TPO).Five PAX8 mutations were found, yielding a mutation prevalence of 5/453 (1.1%). We selected two mutations in the critical paired domain of PAX8 and generated mutants D94N and G41V. We demonstrated G41V was unable to bind the specific sequence in the promoters of TG and TPO and activate them. D94N could bind to TG and TPO promoters and normally activate the TG promoter transcription but not the TPO promoter transcription. We also demonstrated a dominant negative role of the PAX8 mutants in impairing the function of the wild-type PAX8.We for the first time documented the prevalence and characterized the function of PAX8 mutations in CH in Chinese population. The study specifically demonstrated the role of novel mutations D94N and G41V in impairing the function of PAX8, providing further evidence for genetic PAX8 defects as a disease mechanism in CH.
| S-EPMC5352434 | biostudies-literature
Project description:Congenital Hypothyroidism occurs in 1:3500 live births and is therefore the most common congenital endocrine disorder. A spectrum of defective thyroid morphology, termed thyroid dysgenesis, represents 80% of permanent CH cases. Although several candidate genes have been implicated in thyroid development, comprehensive screens failed to detect mutation carriers in a significant number of patients with non-syndromic TD. Due to the sporadic occurrence of TD, de novo chromosomal rearrangements are conceivably representing one of the molecular mechanisms participating in its aetiology. Recently, the use of array CGH technique has provided the ability to map these variations genomewide with high resolution. We performed an array CGH screen of 74 TD patients to determine the role of copy number variants (CNV) in the aetiology of the disease. We identified novel CNVs in 8.75% of all patients that have not been described as frequent variations in the healthy population. Affected patients presented with athyreosis or thyroid hypoplasia and in one case with associated heart malformation. We selected 74 patients with thyroid dysgenesis for array CGH analysis. All individuals were detected in neonatal screening programs and abnormal thyroid gland morphology was subsequently confirmed by ultrasound examination. Intragenic mutations in NKX2-1, FOXE1 and NKX2.5 had been previously excluded in phenotype characteristic individuals. PAX8 mutations were excluded in all patients with hypoplastic thyroids by direct sequencing of the coding exons 1-11. The study was approved by the local ethics committee. Genomic DNA of all subjects as well as of healthy controls was isolated from peripheral blood leucocytes using the Qiagen DNA blood mini kit (Qiagen, Hilden, Germany). Array-comparative genomic hybridization was carried as described previously {Erdogan, 2006 #142; Pinkel, 1998 #151}. In brief, sonicated patient- and control DNA was labeled by random priming with Cy3-dUTP and Cy5-dUTP (Bioprime Array CGH, Invitrogen, Carlsbad, CA), respectively, and hybridized onto a submegabase resolution tiling path BAC array, consisting of ~ 36 000 BAC clones obtained from several sources as described elsewhere {Fiegler, 2003 #198; Ishkanian, 2004 #196; Krzywinski, 2004 #197} . Step-by-step protocols are also provided at http://www.molgen.mpg.de/~abt_rop/molecular_cytogenetics/. Arrays were scanned with the G2565BA Agilent Microarray Scanner System (resolution 10 µm; PMT 100 % for Cy3/Cy5, respectively) (Agilent Inc. Santa Clara, CA) and analyzed using GENEPIX Pro 5.0 Software. Analysis and visualization of array CGH data were performed with our software package CGHPRO {Chen, 2005 #143}. For the assessment of copy number gains and losses, we used conservative log2 ratio thresholds of 0.3 and -0.3, respectively. Deviant signal intensity ratios involving three or more consecutive BAC clones were considered to be potentially pathogenic, unless they were covered by more than one known DNA copy number variant, as listed in the Database of Genomic Variants (http://projects.tcag.ca/variation/) or covered by > 50% of their length at least once in our reference set of 600 samples. Potentially pathogenic CNVs were verified by array CGH on a 244k oligonucleotide array from Agilent following the manufacturer’s instructions (Protocol-No. G4410-90010). Confirmed CNVs were tested for inheritance by co-hybridization of parental DNA on BAC arrays as described above. All chromosome coordinates are referring to the UCSC Genome Browser Assembly May 2004 (hg17/ NCBI Build 35; available at: http://genome.ucsc.edu/cgi-bin/hgGateway?hgsid=99195739&clade=vertebrate&org=Human&db=hg17). Cytoscape {Shannon, 2003 #201} was used for the elucidation of potential interactions between genes within the intervals of interest.
2010-05-31 | E-GEOD-18152 | biostudies-arrayexpress
Project description:Background: The etiology, course, and most appropriate management of borderline congenital hypothyroidism (CH) are poorly defined, such that the optimal threshold for diagnosis with bloodspot screening thyrotropin (bsTSH) measurement remains controversial. Dual oxidase 2 (DUOX2) mutations may initially cause borderline elevation of bsTSH, which later evolves into significant hypothyroidism on venous blood measurement. It was hypothesized that mutations in both DUOX2 and its accessory protein DUOXA2 may occur frequently, even in patients with borderline bsTSH elevation, such that higher diagnostic thresholds in bsTSH screening may fail to detect such cases, with consequent risk of undiagnosed neonatal hypothyroidism of sufficient magnitude to require thyroxine therapy. This study aimed to investigate the frequency and characteristics of DUOX2 and DUOXA2 mutations in a borderline CH cohort. Methods: A cross-sectional study of patients with borderline CH was undertaken at Great Ormond Street Hospital, a tertiary British pediatric center. DUOX2 was sequenced in 52 patients with a bsTSH of 6-19.9 mIU/L, venous TSH of >25 mIU/L, and eutopic thyroid gland in situ. DUOXA2 was sequenced in DUOX2 mutation-negative cases, and novel DUOXA2 mutations were functionally characterized. Results: A total of 26 (50%) patients harbored likely pathogenic mutations in DUOX2 (n = 20; 38%) or DUOXA2 (n = 6; 12%), including novel gene variants (DUOX2, n = 3; DUOXA2, n = 7). Two recurrent DUOX2 mutations (p.Q570L, p.F966Sfs*29) occurred frequently in population databases (MAF ≥0.01). Despite bsTSH being <10 mIU/L in 46% of DUOX2 and DUOXA2 mutation-positive cases, venous free thyroxine levels in these patients were in the moderate CH range (M = 9.3 pmol/L, range <3.9-15.8 pmol/L), Conclusions: Targeted DUOX2 and DUOXA2 sequencing in a borderline CH cohort has a high diagnostic yield. These findings might argue for a lowering of bsTSH thresholds, but follow-up studies are required to assess whether cases with borderline bsTSH harboring DUOX2/DUOXA2 mutations will benefit from an early diagnosis and subsequent levothyroxine treatment.
| S-EPMC6588112 | biostudies-literature
Project description:Congenital central hypothyroidism (C-CH) is a rare disease in which thyroid hormone deficiency is caused by insufficient thyrotropin (TSH) stimulation of a normally-located thyroid gland. Most patients with C-CH have low free thyroxine levels and inappropriately low or normal TSH levels, although a few have slightly elevated TSH levels. Autosomal recessive TSH deficiency and thyrotropin-releasing hormone receptor-inactivating mutations are known to be genetic causes of C-CH presenting in the absence of other syndromes. Recently, deficiency of the immunoglobulin superfamily member 1 (IGSF1) has also been demonstrated to cause C-CH. IGSF1 is a plasma membrane glycoprotein highly expressed in the pituitary. Its physiological role in humans remains unknown. IGSF1 deficiency causes TSH deficiency, leading to hypothyroidism. In addition, approximately 60% of patients also suffer a prolactin deficiency. Moreover, macroorchidism and delayed puberty are characteristic features. Thus, although the precise pathophysiology of IGSF1 deficiency is not established, IGSF1 is considered to be a new factor controlling growth and puberty in children.
| S-EPMC4208260 | biostudies-literature
Project description:AimsTo determine the incidence of congenital toxoplasmosis in Colombian newborns from 19 hospital or maternal child health services from seven different cities of five natural geographic regions (Caribbean, Central, Andean, Amazonia and Eastern).Materials and methodsWe collected 15,333 samples from umbilical cord blood between the period of March 2009 to May 2010 in 19 different hospitals and maternal-child health services from seven different cities. We applied an IgM ELISA assay (Vircell, Spain) to determine the frequency of IgM anti Toxoplasma. The results in blood cord samples were confirmed either by western blot and repeated ELISA IgM assay. In a sub-sample of 1,613 children that were negative by the anti-Toxoplasma IgM assay, the frequency of specific anti-Toxoplasma IgA by the ISAGA assay was determined. All children with positive samples by IgM, IgA, clinical diagnosis or treatment during pregnancy were recalled for confirmatory tests after day 10 of life.Results61 positive samples for specific IgM (0.39%) and 9 positives for IgA (0.5%) were found. 143 questionnaires were positive for a clinical diagnosis or treatment for toxoplasmosis during pregnancy. 109 out of the 218 children that had some of the criteria for postnatal confirmatory tests were followed. Congenital toxoplasmosis infection was confirmed in 15 children: 7 were symptomatic, and three of them died before the first month of life (20% of lethality). A significant correlation was found between a high incidence of markers for congenital toxoplasmosis and higher mean annual rainfall for the city.ConclusionsIncidence for congenital toxoplasmosis is significantly different between hospitals or maternal child health services from different cities in Colombia. Mean annual rainfall was correlated with incidence of congenital toxoplasmosis.
| S-EPMC3104965 | biostudies-literature
Project description:Congenital Hypothyroidism occurs in 1:3500 live births and is therefore the most common congenital endocrine disorder. A spectrum of defective thyroid morphology, termed thyroid dysgenesis, represents 80% of permanent CH cases. Although several candidate genes have been implicated in thyroid development, comprehensive screens failed to detect mutation carriers in a significant number of patients with non-syndromic TD. Due to the sporadic occurrence of TD, de novo chromosomal rearrangements are conceivably representing one of the molecular mechanisms participating in its aetiology. Recently, the use of array CGH technique has provided the ability to map these variations genomewide with high resolution. We performed an array CGH screen of 74 TD patients to determine the role of copy number variants (CNV) in the aetiology of the disease. We identified novel CNVs in 8.75% of all patients that have not been described as frequent variations in the healthy population. Affected patients presented with athyreosis or thyroid hypoplasia and in one case with associated heart malformation.
2010-06-01 | GSE18152 | GEO