Novel truncating thyroglobulin gene mutations associated with congenital hypothyroidism
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ORIGINAL ARTICLE
Novel truncating thyroglobulin gene mutations associated with congenital hypothyroidism Hakan Cangul • Kristien Boelaert • Murat Dogan Yaman Saglam • Michaela Kendall • Timothy G. Barrett • Eamonn R. Maher
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Received: 8 May 2013 / Accepted: 26 July 2013 / Published online: 15 August 2013 Ó Springer Science+Business Media New York 2013
diagnosis and classification of CH, and also adds up to the limited number of nonsense TG mutations in the literature. It also suggests a new clinical testing strategy using nextgeneration sequencing in all primary CH cases.
Abstract Mutations in the thyroglobulin (TG) gene have been reported to cause congenital hypothyroidism (CH) and we have been investigating the genetic architecture of CH in a large cohort of consanguineous/multi-case families. Our aim in this study was to determine the genetic basis of CH in four affected individuals coming from two separate consanguineous families. Since CH is usually inherited in autosomal recessive manner in consanguineous/multi-case families, we adopted a two-stage strategy of genetic linkage studies and targeted sequencing of the TG gene. First we investigated the potential genetic linkage of families to any known CH locus using microsatellite markers and then determined the pathogenic mutations in linked-genes by Sanger sequencing. Both families showed potential linkage to TG locus and we detected two previously unreported nonsense TG mutations (p.Q630X and p.W637X) that segregated with the disease status in both families. This study highlights the importance of molecular genetic studies in the definitive
Introduction
H. Cangul (&) Department of Medical Genetics, Bahcesehir University School of Medicine, Istanbul, Turkey e-mail: [email protected]
M. Kendall Department of Child Health, Division of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK
K. Boelaert Centre for Endocrinology, Diabetes and Metabolism, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK
T. G. Barrett Centre for Rare Diseases and Personalised Medicine, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK
M. Dogan Division of Paediatric Endocrinology, Faculty of Medicine, Yuzuncu Yil University, Van, Turkey
E. R. Maher Academic Department of Medical Genetics, University of Cambridge Clinical School, Cambridge, UK
Y. Saglam Centre for Genetic Diagnosis, Medical Park Goztepe Hospital, Istanbul, Turkey
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Keywords Thyroglobuline Mutation Congenital hypothyroidism Dyshormonogenesis
Congenital hypothyroidism (CH) is a relatively common disorder in newborn babies with an incidence of 1 in about 3,500 live births [1]. It causes intellectual disability and growth delay if untreated. CH is mostly sporadic but familial cases occur and 16 genes have been implicated in the pathogenesis of inherited CH to date (Table 1). Nine of these genes are associated with congenital non-goitrous hypothyroidism (CHNG) phenotype w
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