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Manassawee Korwutthikulrangsri Department of Medicine, University of Chicago, Chicago, Illinois, USA
Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand

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Chrysoula Dosiou Department of Medicine, Stanford University School of Medicine, Stanford, California, USA

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Alexandra M. Dumitrescu Department of Medicine, University of Chicago, Chicago, Illinois, USA
Committee on Molecular Metabolism and Nutrition, University of Chicago, Chicago, Illinois, USA

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Samuel Refetoff Department of Medicine, University of Chicago, Chicago, Illinois, USA
Department of Pediatrics, University of Chicago, Chicago, Illinois, USA
Committee on Genetics, University of Chicago, Chicago, Illinois, USA

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Background: Resistance to thyroid hormone beta (RTHβ) is characterized by elevated thyroid hormone and unsuppressed thyroid-stimulating hormone (TSH), caused by thyroid hormone receptor beta gene (THRB) defects. Most mutations producing RTHβ phenotype are located in CG-rich regions of THRB, encoding the T3-binding and hinge domains of the receptor. However, a region encompassing codons 384–425 is virtually devoid of RTHβ-causing mutations, termed “cold region.” Case: A 49-year-old woman was diagnosed with Hashimoto thyroiditis in her twenties, and levothyroxine (LT4) was initiated. During LT4 treatment she had slightly elevated free thyroxine and TSH levels, suggesting the possibility of RTHβ. Results: Sequencing of THRB identified a heterozygous missense variant c.1154G>A producing p.G385E in the proband. Since this variant of unknown significance (VUS) has not been reported in RTHβ individuals and considering its location in the “cold region” of THRB, we questioned its relevance. In silico functional prediction algorithms showed conflicting results: PolyPhen-2 predicted this VUS to be probably damaging with a score of 1.000, while SIFT predicted it to be tolerated with a score of 0.07, thus making additional investigations necessary. Genotyping of family members revealed that the proband’s mother and sister, without RTHβ phenotype, also harbored the same variant. This indicates that the THRB G385E variant is unlikely to manifest RTHβ phenotype and confirms its “cold” status. Conclusions: This study illustrates that assigning causality of a THRB VUS for RTHβ based only on in silico prediction algorithms is not always fully reliable. Additional phenotype-genotype segregation in family members can assist in predicting functional consequences of missense mutations.

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Theodora Pappa Departments of Medicine, Chicago, IL, USA

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Lars C. Moeller Department of Endocrinology and Division of Laboratory Research, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

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Deborah V. Edidin Department of Pediatrics, Feinberg School of Medicine Northwestern University, Chicago, IL, USA

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Silvana Pannain Departments of Medicine, Chicago, IL, USA

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Samuel Refetoff Departments of Medicine, Chicago, IL, USA
Departments of Pediatrics, Chicago, IL, USA
Departments of Committee on Genetics, The University of Chicago, Chicago, IL, USA

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Background: Thyroxine-binding globulin (TBG) is the major thyroid hormone transport protein in serum. Located on the long arm of the X chromosome, TBG (SERPINA7) gene mutations most commonly produce inherited partial TBG deficiency (TBG-PD). Objective: We report a novel TBG variant associated with TBG-PD identified in 2 different families of Ashkenazi origin residing in greater Chicago. Methods: Family 1: The proband was 12.6 years old when she presented for delayed puberty and was placed on L-T<sub>4</sub>. Although her serum TSH normalized, her serum T<sub>4</sub> remained low. Affected family members had low total T<sub>4</sub> and T<sub>3</sub>, but a normal free T<sub>4</sub> index, even when serum TSH concentrations were normal. Family 2: A 71-year-old male presented with a history of a nonfunctioning pituitary adenoma and normal pituitary axes except for low total T<sub>4</sub> and T<sub>3</sub>. His brother had a similar thyroid phenotype. Results: Following direct DNA sequencing, both index patients were found to carry a missense mutation in the TBG gene (c.751T>G) producing p.V215G. The proposita of family 1 was heterozygous and the proband in family 2 was hemizygous for the mutation. Isoelectric focusing showed no alteration in the TBG isoforms and in vitro expression demonstrated a TBG with reduced affinity for T<sub>4</sub>. Conclusions: We report a novel mutation in the TBG gene in 2 unrelated families that produces a molecule with reduced affinity for T<sub>4</sub> resulting in low serum T<sub>4</sub>. However, the physical properties of the mutant molecule remained unaltered as determined by isoelectric focusing.

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David Shaki Pediatric Endocrinology Unit, Saban Pediatric Medical Center for Israel, Beer Sheva, Israel
Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel

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Marina Eskin-Schwartz Genetics Institute at Soroka University Medical Center and the Morris Kahn Laboratory of Human Genetics, National Center for Rare Diseases, at the Faculty of Health Sciences and National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva, Israel

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Noam Hadar Genetics Institute at Soroka University Medical Center and the Morris Kahn Laboratory of Human Genetics, National Center for Rare Diseases, at the Faculty of Health Sciences and National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva, Israel

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Emily Bosin Endocrinology Lab, Soroka University Medical Center, Beer Sheva, Israel

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Lior Carmon Pediatric Endocrinology Unit, Saban Pediatric Medical Center for Israel, Beer Sheva, Israel
Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel

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Samuel Refetoff Departments of Medicine and Pediatrics and the Committee on Genetics, The University of Chicago, Chicago, Illinois, USA

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Eli Hershkovitz Pediatric Endocrinology Unit, Saban Pediatric Medical Center for Israel, Beer Sheva, Israel
Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel

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Ohad S Birk Genetics Institute at Soroka University Medical Center and the Morris Kahn Laboratory of Human Genetics, National Center for Rare Diseases, at the Faculty of Health Sciences and National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Beer Sheva, Israel

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Alon Haim Pediatric Endocrinology Unit, Saban Pediatric Medical Center for Israel, Beer Sheva, Israel
Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel

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Objective

Bi-allelic loss-of-function mutations in TSHB, encoding the beta subunit of thyroid-stimulating hormone (TSH), cause congenital hypothyroidism. Homozygosity for the TSHB p.R75G variant, previously described in South Asian individuals, does not alter TSH function but abrogates its detection by some immune detection-based platforms, leading to erroneous diagnosis of hyperthyroidism. We set out to identify and determine the carrier rate of the p.R75G variant among clinically euthyroid Bene Israel Indian Jews, to examine the possible founder origin of this variant worldwide, and to determine the phenotypic effects of its heterozygosity.

Design

Molecular genetic studies of Bene Israel Jews and comparative studies with South Asian cohort.

Methods

TSHB p.R75G variant tested by Sanger sequencing and restriction fragment length polymorphism (RFLP). Haplotype analysis in the vicinity of the TSHB gene performed using SNP arrays.

Results

Clinically euthyroid individuals with low or undetectable TSH levels from three apparently unrelated Israeli Jewish families of Bene Israel ethnicity, originating from the Mumbai region of India, were found heterozygous or homozygous for the p.R75G TSHB variant. Extremely high carrier rate of p.R75G TSHB in Bene Israel Indian Jews (~4%) was observed. A haplotype block of 239.7 kB in the vicinity of TSHB shared by Bene Israel and individuals of South Asian origin was detected.

Conclusions

Our findings highlight the high prevalence of the R75G TSHB variant in euthyroid Bene Israel Indian Jews, demonstrate that heterozygosity of this variant can cause erroneous detection of subnormal TSH levels, and show that R75G TSHB is an ancient founder variant, delineating shared ancestry of its carriers.

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Luca Persani L Persani, Medical Biotechnologies and Translational Medicine, University of Milan, Milano, 20149, Italy

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Patrice Rodien P Rodien, EDN, Centre Hospitalier Universitaire d'Angers, Angers, 49933, France

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Carla Moran C Moran, Diabetes & Endocrinology Section, Beacon Hospital, Sandyford, Ireland

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W. Edward Visser W Visser, Department of Internal Medicine and Rotterdam Thyroid Center, Erasmus Medical Center, Rotterdam, Netherlands

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Stefan Groeneweg S Groeneweg, Department of Internal Medicine and Rotterdam Thyroid Center, Erasmus Medical Center, Rotterdam, Netherlands

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Robin P. Peeters R Peeters, Department of Internal Medicine and Rotterdam Thyroid Center, Erasmus Medical Center, Rotterdam, Netherlands

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Samuel Refetoff S Refetoff, Departments of Medicine and Pediatrics, The University of Chicago, Chicago, 60637-1476, United States

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Mark Gurnell M Gurnell, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom of Great Britain and Northern Ireland

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Paolo Beck-Peccoz P Beck-Peccoz, Department of Medical Biotechnology and Translational Medicine, University of Milan, Milano, Italy

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Krishna Chatterjee K Chatterjee, Institute of Metabolic Science, University of Cambridge, Cambridge, CB2 0QQ, United Kingdom of Great Britain and Northern Ireland

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Impaired sensitivity to thyroid hormones encompasses disorders with defective transport of hormones into cells, reduced hormone metabolism and resistance to hormone action. Mediated by heritable single gene defects, these rare conditions exhibit different patterns of discordant thyroid function associated with multisystem phenotypes. In this context, challenges include ruling out other causes of biochemical discordance, making a diagnosis using clinical features together with identification of pathogenic variants in causal genes and managing these rare disorders with a limited evidence base. For each condition, the present guidelines aim to inform clinical practice by summarising key clinical features and useful investigations, criteria for molecular genetic diagnosis and pathways for management and therapy. Specific, key recommendations were developed by combining the best research evidence available with the knowledge and clinical experience of panel members, to achieve a consensus.

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Samuel Refetoff Departments of Medicine, The University of Chicago, Chicago, Ill., USA
Departments of Pediatrics, The University of Chicago, Chicago, Ill., USA
Genetics, The University of Chicago, Chicago, Ill., USA

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J.H. Duncan Bassett Department of Medicine, Imperial College London, London, UK

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Paolo Beck-Peccoz Department of Clinical Sciences and Community Health, University of Milan
Fondazione Ca' Granda Policlinico, Milan, Italy

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Juan Bernal Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas-Universidad Autonoma de Madrid and Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain

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Gregory Brent Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Calif., USA

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Krishna Chatterjee Wellcome-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, UK

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Leslie J. De Groot Thyroidmanager and Endotext, South Dartmouth, Mass

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Alexandra M. Dumitrescu Departments of Medicine, The University of Chicago, Chicago, Ill., USA

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J. Larry Jameson Raymond and Ruth Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa

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Peter A. Kopp Division of Endocrinology, Metabolism, and Molecular Medicine and Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Ill., USA

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Yoshiharu Murata Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan

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Luca Persani Department of Clinical Sciences and Community Health, University of Milan
Istituto Auxologico Italiano, Milan, Italy

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Jacques Samarut Ecole Normale Supérieure de Lyon, Lyon, France

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Roy E. Weiss Departments of Medicine, The University of Chicago, Chicago, Ill., USA
Departments of Pediatrics, The University of Chicago, Chicago, Ill., USA

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Graham R. Williams Department of Medicine, Imperial College London, London, UK

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Paul M. Yen Laboratory of Hormone Action, Singapore Institute of Clinical Sciences, Singapore, Singapore

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