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Novel truncating thyroglobulin gene mutations associated with congenital hypothyroidism

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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 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 next-generation sequencing in all primary CH cases.

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Acknowledgments

This study was funded by European Union under its Framework 7 programme, FP7-PEOPLE-2009-Marie Curie-IEF, and by Queen Elisabeth Hospital Birmingham Foundation Trust. We also thank the families for their participation in this study.

Conflict of interest

Authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Medical Genetics, Bahcesehir University School of Medicine, Istanbul, Turkey

    Hakan Cangul

  2. Centre for Endocrinology, Diabetes and Metabolism, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK

    Kristien Boelaert

  3. Division of Paediatric Endocrinology, Faculty of Medicine, Yuzuncu Yil University, Van, Turkey

    Murat Dogan

  4. Centre for Genetic Diagnosis, Medical Park Goztepe Hospital, Istanbul, Turkey

    Yaman Saglam

  5. Department of Child Health, Division of Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK

    Michaela Kendall

  6. Centre for Rare Diseases and Personalised Medicine, School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK

    Timothy G. Barrett

  7. Academic Department of Medical Genetics, University of Cambridge Clinical School, Cambridge, UK

    Eamonn R. Maher

Authors
  1. Hakan Cangul
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  2. Kristien Boelaert
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  3. Murat Dogan
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  4. Yaman Saglam
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  5. Michaela Kendall
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  6. Timothy G. Barrett
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  7. Eamonn R. Maher
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Correspondence to Hakan Cangul.

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Cangul, H., Boelaert, K., Dogan, M. et al. Novel truncating thyroglobulin gene mutations associated with congenital hypothyroidism. Endocrine 45, 206–212 (2014). https://doi.org/10.1007/s12020-013-0027-7

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  • DOI: https://doi.org/10.1007/s12020-013-0027-7

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