Elsevier

Journal of Autoimmunity

Volume 86, January 2018, Pages 116-119
Journal of Autoimmunity

Monogenic Hashimoto thyroiditis associated with a variant in the thyroglobulin (TG) gene

https://doi.org/10.1016/j.jaut.2017.09.003Get rights and content

Highlights

Abstract

Background

Risk of autoimmune thyroid disease (AITD) is strongly heritable. Multiple genes confer increased risk for AITD, but a monogenic origin has not yet been described. We studied a family with apparent autosomal dominant, early onset Hashimoto thyroiditis.

Methods

The family was enrolled in an IRB-approved protocol. Whole exome sequencing was used to study the proband and an affected sibling. The identified variant was studied in other family members by Sanger sequencing.

Results

We identified a previously unreported splice site variant in the thyroglobulin gene (TG c.1076-1G > C). This variant was confirmed in all affected family members who underwent testing, and also noted in one unaffected child. The variant is associated with exon 9 skipping, resulting in a novel in-frame variant transcript of TG.

Conclusion

We discovered a monogenic form of AITD associated with a splice site variant in the thyroglobulin gene. This finding raises questions about the origins of thyroid autoimmunity; possible explanations include increased immunogenicity of the mutated protein or thyroid toxicity with secondary development of anti-thyroid antibodies. Further study into the effects of this variant on thyroid function and thyroid autoimmunity are warranted.

Introduction

Autoimmune thyroid disease (AITD) includes both Graves disease and Hashimoto thyroiditis and is characterized by autoantibodies to thyroglobulin and thyroperoxidase. The etiology of AITD is complex and multifactorial [1]. Like many other autoimmune conditions, AITD disproportionately affects females and onset is in early adulthood, suggesting that hormonal and environmental factors are involved [2]. AITD is also known to be strongly heritable, and families with multiple affected siblings were first described in the 1960s [3].

Multiple genes have been identified through linkage analyses and genome-wide association studies to contribute to AITD susceptibility. These include immune regulatory genes such as CTLA4, CD40, PTPN22, FOXP3, and CD25, which have also been implicated in the suspectibility toward other autoimmune diseases [4]. The HLA-DR3 allele also confers significant risk for AITD, perhaps by influencing presentation of thyroid self-antigen [5].

Variants in thyroid-specific genes, including TSHR (thyroid-stimulating hormone receptor) and TG (thyroglobulin) are also associated with susceptibility to AITD [6], [7]. Thyroglobulin, as the precursor for thyroid hormone, is the predominant protein within the thyroid gland [8]. Intronic and exonic TG polymorphisms have previously been linked to both Graves disease as well as Hashimoto thyroiditis phenotypes [9], [10], [11]. The TG SNPs previously described in association with AITD confer a relatively modest increase in risk; these gene variants are also found in healthy populations without AITD or anti-thyroid antibodies [10]. The mechanism by which these variants lead to autoimmunity is not known.

In this study, we used whole exome sequencing to evaluate an extended family with autosomal dominant inheritance of Hashimoto thyroiditis. We identified an extremely rare splice site variant in TG in affected members.

Section snippets

Subject recruitment

The proband and affected and unaffected family members were enrolled in an IRB-approved study at Boston Children's Hospital. Informed consent was obtained from all enrolled subjects.

Exome sequencing

Total genomic DNA was extracted from peripheral blood mononuclear cells using QIAmp DNA Mini Kit (Qiagen). DNA from the proband and one affected cousin was sent for whole exome sequencing (WES). WES was provided by the Yale University Centers for Mendelian Genomics on an Illumina HiSeq 2000. Libraries (TruSeq DNA v2

Clinical phenotype of familial Hashimoto thyroiditis

The proband was diagnosed with Hashimoto thyroiditis at age 6 years 10 months after presenting with fatigue, frequent complaints of feeling cold, and a subtle decrease in growth velocity. Thyroid stimulating hormone (TSH) was elevated at 10.62 IU/mL. Anti-thyroid antibodies were markedly elevated, with anti-thyroglobulin 275 IU/mL and anti-thyroperoxidase 175 IU/mL. Notably, the patient's mother had also been diagnosed with Hashimoto thyroiditis at age 8 years. Further review of the family

Discussion

To our knowledge, this is the first description of a family with true Mendelian inheritance of autoimmune thyroid disease (AITD). While familial AITD is a commonly recognized phenomenon, distinctive features of this family include the early age of onset, the lack of female predominance, and the fact that clinical phenotype was limited to Hashimoto thyroiditis and not Graves disease. Using a whole exome sequencing approach, we identified an autosomal dominant mutation in the thyroglobulin gene

Conclusion

We describe here a family with early onset autoimmune thyroid disease associated with a splice site variant in the thyroglobulin gene. Functional studies are necessary to understand how this mutation leads to autoimmunity. Further exploration of mechanism may yield important insights in protein biochemistry and antigen presentation that may be applicable to other autoimmune conditions.

Competing interests declaration

The authors have no competing interests to declare.

Acknowledgements

We would like to thank the extended family for their participation in this case study and the authors gratefully acknowledge assistance and support from The Manton Center for Orphan Disease Research Gene Discovery Core. The work was made possible by National Institute of Health (NIH) grants R01 AR068429 (PBA), U19 HD077671 (PBA), and 5R01AI065617 (TAC). Sanger sequencing was performed by the Molecular Genetics Core Facility of the IDDRC at Boston Children's Hospital, supported by National

References (21)

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