Congenital goitrous hypothyroidism due to thyroglobulin deficiency associated with angioinvasive follicular thyroid carcinoma: comprehensive and integral analysis of the p.Cys1897_Glu1900 deletion.

PURPOSE: This study focused on elucidating the molecular basis underlying the clinical phenotype of a patient presenting with congenital hypothyroidism (CH), goiter, and angioinvasive follicular thyroid carcinoma. METHODS: The index patient underwent comprehensive clinical, biochemical, and imaging assessments. DNA sequencing, genotyping, and bioinformatics analyses were subsequently performed. RESULTS: Whole exome sequencing (WES) of peripheral blood leukocyte and tumor tissue DNA, together with confirmatory Sanger sequencing, revealed a previously undescribed homozygous inactivating thyroglobulin (TG) variant, NM_003235.5:c.5688_5699delTTGTGTGCAGGA [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. 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 cysteine1897-valine1898-glutamine1899-glutamic acid1900. Although the deletion does not cause a frameshift, the loss of cysteine1897 disrupts a critical disulfide bond, thereby altering the three-dimensional structure of TG. 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. Single-nucleotide variant (SNV) and indel analysis across chromosome 8 identified a continuous homozygous block of approximately 17.7 Mb encompassing the TG gene, supporting an interpretation consistent with either segmental terminal uniparental isodisomy or a copy neutral loss of heterozygosity arising from recombination. Despite an extensive evaluation of 69 additional candidate genes involved in thyroid physiology, regulatory mechanisms, and the pathogenesis of primary and central CH and goiter, together with 43 genes within pathways recognized for their role in cancer progression and major drivers of thyroid tumorigenesis-using population databases and predictive tools for non synonymous missense variants-no deleterious variants were identified in any of these genes. CONCLUSION: We report a novel deletion that broadens the spectrum of TG variants. This defect impairs T4 synthesis, elevates TSH levels, and-through its mitogenic effect-drives goiter development, while potentially predisposing to angioinvasive follicular thyroid carcinoma.