Angioinvasive follicular thyroid carcinoma in congenital goitrous hypothyroidism due to thyroglobulin deficiency: comprehensive and integral analysis of the p.Cys1897_Glu1900 deletion

The aim of this investigation was to identify and characterize a novel variant in the thyroglobulin ( TG ) gene in a patient presenting with congenital hypothyroidism, goiter, and angioinvasive follicular thyroid carcinoma. The index patient underwent comprehensive clinical, biochemical, and imaging evaluation. DNA sequencing, genotyping, and bioinformatics analyses were performed. Whole-exome sequencing (WES) and Sanger sequencing revealed a previously undescribed biallelic inactivating TG variant, NM_003235.5:c.5688_5699del TTGTGTGCAGGA [NP_003226.4:p.Cys1897_Glu1900del]. Family segregation analysis demonstrated that the healthy mother and half-sister were heterozygous carriers of the NM_003235.5:c.5688_5699del variant, while paternal DNA was not available for sequence analysis. DECoN software analysis of WES data confirmed the homozygous state in the index patient, with no evidence of allelic deletion or duplication in the TG locus on chromosome 8. The deletion occurs immediately after the first nucleotide of exon 31, within the TG type 3a-2 domain of region III, removing 12 nucleotides that encode the amino acids Cysteine–Valine–Glutamine–Glutamic Acid. Although the deletion does not cause a frameshift, the loss of cysteine disrupts a critical disulfide bond, thereby altering the three-dimensional structure of TG. Previous studies have shown that cysteine deletions in TG result in intracellular retention of the protein, impairing its trafficking through the ER–Golgi–colloid axis. Splicing predictor analysis excluded canonical splice site disruption but indicated the loss of an SR protein binding site, which may subtly affect exon recognition or mRNA stability. Additionally, a comprehensive analysis of 36 genes associated with cancer progression and thyroid tumorigenesis was performed using population databases, and non-synonymous missense variants were evaluated with protein prediction tools. No pathogenic variants were detected. In conclusion, we report a novel deletion that expands the spectrum of TG variants. This defect impairs T ₄ synthesis, elevates TSH levels, and—through its mitogenic effect—promotes goiter development and predisposes to angioinvasive follicular thyroid carcinoma.