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

Area of Science:

• Genetics
• Immunology
• Endocrinology

Background:

• Autoimmune thyroid disease (AITD) has a strong genetic component, but a single-gene cause was previously undescribed.
• Hashimoto thyroiditis, an AITD, was studied in a family with suspected autosomal dominant inheritance and early onset.

Purpose of the Study:

• To identify the genetic basis of early-onset Hashimoto thyroiditis in a familial cohort.
• To investigate the potential for a monogenic cause of autoimmune thyroid disease.

Main Methods:

• Whole exome sequencing was performed on the proband and an affected sibling.
• A novel splice site variant in the thyroglobulin gene (TG) was identified and confirmed using Sanger sequencing in family members.

Main Results:

• A previously unreported splice site variant (TG c.1076-1G>C) in the thyroglobulin gene was identified.
• This variant leads to exon 9 skipping, producing a novel in-frame variant transcript of thyroglobulin.
• The variant was present in all affected family members tested and one unaffected child.

Conclusions:

• A monogenic form of autoimmune thyroid disease associated with a thyroglobulin gene splice site variant has been discovered.
• This finding suggests potential mechanisms for thyroid autoimmunity, including protein immunogenicity or thyroid toxicity.
• Further research is needed to elucidate the precise effects of this variant on thyroid function and autoimmunity.