Functional impact of a novel intronic TG variant in congenital goiter and thyroid dyshormonogenesis

INTRODUCTION: Thyroglobulin (TG) is essential for the biosynthesis of thyroid hormones. Biallelic pathogenic variants in the TG gene cause primary congenital hypothyroidism due to dyshormonogenesis (DHG), which often presents with congenital goiter. Here, we report a novel homozygous intronic TG variant, identified in a family with multiple cases of congenital goiter, and demonstrate its pathogenicity using cDNA sequencing. CASE PRESENTATION: The proband, a 15.5-year-old male, presented with a thyroid nodule and had a history of congenital goiter. He had been treated with levothyroxine since birth. Serum TG concentration was markedly low. Thyroid ultrasound revealed diffuse heterogeneity and a solid nodule. Thyroidectomy was performed due to atypia of undetermined significance on fine-needle aspiration biopsy, and histopathological examination revealed adenomatoid hyperplasia. Analysis of the proband revealed a novel homozygous c.5686+3A>C variant in TG (NM_003235). In silico analysis predicted a splice-altering variant, and the variant was absent from gnomAD. Analysis of cDNA sequencing confirmed that this variant causes exon 30 skipping, leading to an in-frame deletion and presumably a nonfunctional TG protein. In a subsequent pregnancy evaluated during the course of this case, fetal goiter was identified and treated with intra-amniotic levothyroxine. CONCLUSION: This study reports a novel intronic TG variant causing aberrant splicing, thereby expanding the molecular spectrum of primary congenital hypothyroidism and emphasizing the importance of early genetic diagnosis for effective counseling and prevention of recurrence.