Novel DIO1 gene mutation acting as phenotype modifier for novel compound heterozygous TPO gene mutations causing congenital hypothyroidism

Acute liver injury (ALI) in children is a life-threatening event, and a definitive etiology can be identified in approximately 50% of cases. Neuroblastoma amplified sequence (NBAS) gene mutations have been associated with a broad phenotypic spectrum of this disease, ranging from recurrent episodes of fever-induced liver injuries to multiorgan involvement, including frequent infections as well as skeletal and immunological abnormalities. Here, we describe an adolescent female with a confirmed compound heterozygous NBAS gene mutation who presented with an episode of ALI complicated by severe acute kidney injury (AKI). The kidney injury was most probably driven by an intrinsic insult, as noted by elevated neutrophil gelatinase-associated lipocalin levels and a kidney biopsy demonstrating severe tubular damage consistent with acute tubular necrosis. While the patient’s liver function and mental status showed significant improvement with supportive care, recovery of kidney function was delayed, and the patient required acute hemodialysis. We suggest a causative relation between the NBAS gene mutation and severe AKI.

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Thyroglobulin Gene Mutation with Cold Nodule on Thyroid Scintigraphy

Case Reports in Endocrinology ◽

10.1155/2012/280319 ◽

2012 ◽

Vol 2012 ◽

pp. 1-4 ◽

Cited By ~ 4

Author(s):

Toshio Kahara ◽

Noboru Igarashi ◽

Akira Hishinuma ◽

Yuko Nakanishi ◽

Akio Uchiyama ◽

...

Keyword(s):

Thyroid Carcinoma ◽

Gene Mutation ◽

Congenital Hypothyroidism ◽

Elevated Serum ◽

Gene Mutations ◽

Thyroid Scintigraphy ◽

Serum Thyroglobulin ◽

Hyperplastic Nodule ◽

Thyroglobulin Gene ◽

Cold Nodule

Thyroglobulin gene mutation is a rare cause of congenital hypothyroidism, but thyroglobulin gene mutations are thought to be associated with thyroid cancer development. A 21-year-old Japanese man treated with levothyroxine for congenital hypothyroidism had an enlarged thyroid gland with undetectable serum thyroglobulin despite elevated serum TSH level. The patient was diagnosed with thyroglobulin gene mutation, with compound heterozygosity for Gly304Cys missense mutation and Arg432X nonsense mutation. Ultrasonography showed a hypovascular large tumor in the left lobe that appeared as a cold nodule on thyroid scintigraphy. He underwent total thyroidectomy, but pathological study did not reveal findings of thyroid carcinoma, but rather a hyperplastic nodule with hemorrhage. Strong cytoplasmic thyroglobulin immunostaining was observed, but sodium iodide symporter immunostaining was hardly detected in the hyperplastic nodule. The clinical characteristics of patients with thyroglobulin gene mutations are diverse, and some patients are diagnosed by chance on examination of goiter in adults. The presence of thyroid tumors that appear as cold nodules on thyroid scintigraphy should consider the potential for thyroid carcinoma, if the patient has relatively low serum thyroglobulin concentration in relation to the degree of TSH without thyroglobulin autoantibody.

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Molecular Characterization and Frequencies of Different Genetic Ameliorating Factors in Transfusion Dependent Thalassemia Patients from District Peshawar

Blood ◽

10.1182/blood-2019-130049 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4816-4816

Author(s):

Gulrukh Mehmood ◽

Abid Sohail Taj ◽

Arshi Naz ◽

Tariq Masood Khan

Keyword(s):

Gene Mutation ◽

Conflicts Of Interest ◽

Globin Gene ◽

Severe Disease ◽

Genetic Modifier ◽

Gene Mutations ◽

Clinical Severity ◽

Health Concern ◽

Compound Heterozygous ◽

Globin Genes

Background Thalassemia is one of the most common genetic blood disorders worldwide. The carrier rate of β thalassemia in Pakistan is found to be around 5-7%, rendering it a major health concern. Approximately 5000 children are diagnosed with thalassemia major every year in Pakistan due to consanguineous marriages. More than 200 causative molecular defects have been identified in β-globin genes. About 20 mutations account for 90% of the abnormal β-genes. Clinical severity of β-thalassemia is modified by different factors. The important ones include the type of disease causing mutation and the ability to produce α and γ globin chains. A better understanding of these ameliorating factors may have a significant impact on disease management. Objectives 1. To re-assess diagnoses among local multi-transfused thalassemia syndrome patients. 2. To determine frequency of various genetic determinants of milder phenotypes of thalassemia among study patients. Methods Transfusion dependent thalassemia patients, upto 15 years age, were enrolled from Fatimid Foundation, Peshawar Pakistan. A comprehensive questionnaire encompassing demographic and clinical data was filled out for each patient. Genetic analyses for 2 alpha (α) and 13 prevalent beta (β) gene mutations and for polymorphisms at Xmn1-HBG2 and BCL11A were carried out on blood samples of the patients at National Institute of Blood Diseases, Karachi Pakistan. The data collected was analysed at Khyber Medical University (KMU) Peshawar Pakistan. Results A total of 54 transfusion dependent thalassemia patients were enrolled into the study. Homozygous or compound heterozygous combinations of β-globin gene mutations were identified in all the study patients. Eleven patients were found to have a co-existing heterozygous α (3.7kb) deletion, two patients had Xmn1-HBG2 polymorphism and 38 had BCL11A polymorphism. Homozygous Fr 8-9 was the most frequent mutation, found in 19 (35.2%) patients. Only 13 patients were found to have isolated β-globin gene mutations. In total, 46 (85.2%) study patients were identified to have an ameliorating genetic factor (a co-existing α-globin gene mutation, an Xmn1-HBG2 polymorphism or a BCL11A polymorphism) besides the main β-globin gene mutation. Conclusion It was concluded that co-existing genetic ameliorating factors are frequently found in transfusion dependent β-thalassemia patients of Peshawar District. These factors impart a milder phenotype to an otherwise severe disease. It is hence suggested that β-thalassemia patients from District Peshawar be screened for these factors and due consideration be paid by the physician in devising management plans. Key Words Thalassemia, Genetic modifier in thalassemia, Transfusion dependent Anaemia, Xmn1 polymorphism Disclosures No relevant conflicts of interest to declare.

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Clinical Characteristics and Gene Mutation Analysis of the Chinese Han Population with Gitelman Syndrome: 3 Case Reports and a Literature Review

Case Reports in Medicine ◽

10.1155/2020/6263721 ◽

2020 ◽

Vol 2020 ◽

pp. 1-6

Author(s):

Xueting Li ◽

Ruofei Chen ◽

Mingwei Chen

Keyword(s):

Gene Mutation ◽

Mutation Analysis ◽

Clinical Characteristics ◽

Clinical Phenotype ◽

Gene Mutations ◽

Gitelman Syndrome ◽

Chinese Patients ◽

Compound Heterozygous ◽

Homozygous Mutation ◽

Gene Mutation Analysis

The present study reported clinical characteristics and the results of gene mutation analysis of 3 Chinese patients with Gitelman syndrome (GS). Three patients manifested with normal blood pressure, recurrent hypokalemia, and metabolic alkalosis. Only case 2 had obvious hypomagnesemia. Gene sequencing showed a compound heterozygous mutation in SCL12A3 in case 1 and a homozygous mutation in SCL12A3 in case 2. Heterozygous mutations in SCL12A3 and CLCNKB were found in case 3. Then, the literature was reviewed. The keyword “Gitelman syndrome” was inputted into the PubMed, Wanfang Database, and CNK to search all Chinese patients with GS diagnosed by gene mutations and to extract complete clinical data from December 1998 to 2018. Finally, a total of 124 cases of GS were included. No significant differences in the levels of serum potassium and magnesium were observed among the different gene mutations, and the serum magnesium levels in adults were lower than those of the juvenile. GS with reduced blood magnesium had a serious clinical phenotype. Therefore, GS had a diverse phenotype, and its final diagnosis required genetic profiling. The relationship of gene mutation and clinical phenotype needed further study.

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Clinical and Genetic Analysis of a Compound Heterozygous Mutation in the Thyroglobulin Gene in a Chinese Twin Family With Congenital Goiter and Hypothyroidism

Twin Research and Human Genetics ◽

10.1375/twin.15.1.126 ◽

2012 ◽

Vol 15 (1) ◽

pp. 126-132 ◽

Cited By ~ 6

Author(s):

Shiguo Liu ◽

Shasha Zhang ◽

Wenjie Li ◽

Aiqing Zhang ◽

Fengguang Qi ◽

...

Keyword(s):

Gene Mutation ◽

Congenital Hypothyroidism ◽

High Performance ◽

Stop Codon ◽

Compound Heterozygous Mutation ◽

Heterozygous Mutation ◽

Compound Heterozygous ◽

Chinese Han ◽

Congenital Goiter ◽

Normal Controls

Mutations in the thyroglobulin (TG) gene, which has an estimated incidence of approximately 1 in 100,000 new-borns, cause autosomal recessive congenital hypothyroidism. The mutational spectrum of the TG gene and the phenotype–genotype correlations have not yet fully been established. We report a compound heterozygous mutation in the TG gene in a Chinese twin family with congenital goiter and hypothyroidism. We also describe the gene mutation associated with the genotype–phenotype of these children with congenital goiter and hypothyroidism. The whole coding sequence of the TG gene was analyzed by direct sequence, and the identified changes in the sequence were tested for benign polymorphism by denaturing high-performance liquid chromatography screening of the mutation and sequencing 200 chromosomes from normal controls. Analysis of the TG gene of the affected twin revealed a compound heterozygous mutation, including a novel missense mutation G2687A, which is predicted to result in a glutamine to arginine substitution at codon 877, and a known nonsense mutation C7006T, predicted to result in an arginine to stop codon at codon 2317. Analysis of 200 normal chromosomes did not identify the same change in healthy subjects. This is the first report of a TG gene mutation in the Chinese Han population. Our study provides further evidence that mutations in the TG gene cause congenital goiter and hypothyroidism, demonstrates genetic heterogeneity of the mutation, and increases our understanding of phenotype–genotype correlations in congenital hypothyroidism.

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SUN-LB133 Analysis of Clinical Characteristics and Gene Mutation in Four Cases of Gitelman Syndrome

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.1988 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Bin Yao

Keyword(s):

Gene Mutation ◽

Metabolic Alkalosis ◽

Clinical Characteristics ◽

Gene Mutations ◽

Gitelman Syndrome ◽

Compound Heterozygous ◽

Homozygous Mutation ◽

Slc12a3 Gene ◽

Renal Tubular Disorder ◽

Renal Tubular

Abstract Gitelman syndrome is an autosomal recessive renal tubular disorder characterized by renal salt wasting with secondary hyperreninemia and hyperaldosteronism, chronic hypokalemia with renal K wasting and metabolic alkalosis, and hypomagnesemia, and hypocalciuria. GS was found to be caused by mutations in SLC12A3 encoding the thiazide-sensitive sodium chloride cotransporter (NCCT) on the apical membrane of distal convoluted tubule. The prevalence worldwide is estimated at approximately 1:40,000, making it one of the most frequent inherited renal tubular disorders. To date, over 400 mutations scattered throughout SLC12A3 have been identified in GS patients. The majority of patients are compound heterozygous for SLC12A3 mutations, but a significant number of GS patients are found to carry only a single SLC12A3 mutation. The type of the SLC12A3 mutation may be a determinant factor in the severity of GS. The purpose of this study is to analyze clinical characteristics and gene mutation in four cases of GS. Methods: Four patients with closely resembling Gitelman syndrome was selected. Results: Six SLCl2A3 gene mutations were found in these four patients. There were one SLCl2A3 homozygous mutation in case 1 and case 3, and two SLCl2A3 heterozygous mutations in case 2 and case 4, respectively. This six gene mutations include missense mutations, frameshift mutations, and nonsense mutations. Four patients were diagnosed with Gitelman syndrome. Case 4 is the most severe with severe hypokalemia, accompanied by ventricular arrhythmias, which may be related to the presence of two SLC12A3 gene mutations in the patient. Conclusions: Four patients in this study were diagnosed with Gitelman syndrome based on their clinical characteristics and genetic testing results. For patients with hyperreninemia and hyperaldosteronism, chronic hypokalemia with renal K wasting and metabolic alkalosis, and hypomagnesemia, and hypocalciuria need to exclude Gitelman syndrome. Key words: Gitelmen Syndrome, Mutations, SlC12A3 gene

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The p.A2215D Thyroglobulin Gene Mutation Leads to Deficient Synthesis and Secretion of the Mutated Protein and Congenital Hypothyroidism with Wide Phenotype Variation

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2009-0150 ◽

2009 ◽

Vol 94 (8) ◽

pp. 2938-2944 ◽

Cited By ~ 26

Author(s):

Viviane Pardo ◽

Jussara Vono-Toniolo ◽

Ileana G. S. Rubio ◽

Meyer Knobel ◽

Roberta F. Possato ◽

...

Keyword(s):

Functional Analysis ◽

Endoplasmic Reticulum ◽

Thyroid Hormone ◽

Congenital Hypothyroidism ◽

Gene Mutations ◽

Cell System ◽

Expression Vectors ◽

Compound Heterozygous ◽

Novel Mutations ◽

Phenotype Variation

Context: Thyroglobulin (TG) is a large glycoprotein and functions as a matrix for thyroid hormone synthesis. TG gene mutations give rise to goitrous congenital hypothyroidism (CH) with considerable phenotype variation. Objectives: The aim of the study was to report the genetic screening of 15 patients with CH due to TG gene mutations and to perform functional analysis of the p.A2215D mutation. Design: Clinical evaluation and DNA sequencing of the TG gene were performed in all patients. TG expression was analyzed in the goitrous tissue of one patient. Human cells were transfected with expression vectors containing mutated and wild-type human TG cDNA. Results: All patients had an absent rise of serum TG after stimulation with recombinant human TSH. Sequence analysis revealed three previously described mutations (p.A2215D, p.R277X, and g.IVS30+1G>T), and two novel mutations (p.Q2142X and g.IVS46-1G>A). Two known (g.IVS30+1G/p.A2215D and p.A2215D/p.R277X) and one novel (p.R277X/g.IVS46-1G>A) compound heterozygous constellations were also identified. Functional analysis indicated deficiency in TG synthesis, reduction of TG secretion, and retention of the mutant TG within the cell, leading to an endoplasmic reticulum storage disease, whereas small amounts of mutant TG were still secreted within the cell system. Conclusion: All studied patients were either homozygous or heterozygous for TG gene mutations. Two novel mutations have been detected, and we show that TG mutation p.A2215D promotes the retention of TG within the endoplasmic reticulum and reduces TG synthesis and secretion, causing mild hypothyroidism. In the presence of sufficient iodine supply, some patients with TG mutations are able to compensate the impaired hormonogenesis and generate thyroid hormone.

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

Frontiers in Endocrinology ◽

10.3389/fendo.2021.695426 ◽

2021 ◽

Vol 12 ◽

Author(s):

Miao Huang ◽

Xiyan Lu ◽

Guoqing Dong ◽

Jianxu Li ◽

Chengcong Chen ◽

...

Keyword(s):

Congenital Hypothyroidism ◽

Detection Rate ◽

Target Genes ◽

Clinical Manifestations ◽

Gene Mutations ◽

Compound Heterozygous ◽

Chinese Han ◽

High Detection Rate ◽

Published Evidence ◽

Pathogenic Genes

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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A clinical case of neonatal diabetes caused by INS gene mutation

Diabetes Mellitus ◽

10.14341/dm9876 ◽

2019 ◽

Vol 22 (2) ◽

pp. 170-176

Author(s):

Rosa A. Atanesyan ◽

Tatyana A. Uglova ◽

Tatyana M. Vdovina ◽

Leonid Ya. Klimov ◽

Marina U. Kostanova ◽

...

Keyword(s):

Gene Mutation ◽

Clinical Case ◽

Molecular Genetic ◽

Genetic Diagnosis ◽

Gene Mutations ◽

Neonatal Diabetes ◽

Compound Heterozygous ◽

Pancreatic Cell ◽

Cell Dysfunction ◽

Genetic Examination

Neonatal diabetes mellitus (NDM) is a severe endocrine pathology diagnosed in children during the first months of life. It comprises rare (1:300 0001:400 000 newborns) metabolic disorders with postnatal pancreatic -cell dysfunction, manifested by hyperglycaemia and hypoinsulinaemia. It is currently established that molecular genetic diagnosis of neonatal diabetes forms can influence treatment and prognosis. Interestingly, most identified mutations in the insulin gene are not inherited, but are sporadic. There is evidence that, in addition to heterozygous INS mutations, NDM can be caused by homozygous or compound-heterozygous mutations. The present article presents the clinical case of a girl with NDM associated with an INS gene mutation. INS gene mutations cause permanent diabetes and require children to undergo genetic examination, especially patients with type 1 diabetes in the absence of antibodies. Currently, there are no data that allow to determine a phenotypic and genotypic portrait of NDM forms or to explain the factors determining their occurrence. Further studies of clinical cases of neonatal diabetes are therefore required to determine the characteristics of NDM subtypes with subsequent disease prognosis.

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