Transcriptome, Methylome and Genomic Variations Analysis of Ectopic Thyroid Glands

BACKGROUND: Congenital hypothyroidism from thyroid dysgenesis (CHTD) is predominantly a sporadic disease characterized by defects in the differentiation, migration or growth of thyroid tissue. Of these defects, incomplete migration resulting in ectopic thyroid tissue is the most common (up to 80%). Germinal mutations in the thyroid-related transcription factors NKX2.1, FOXE1, PAX-8, and NKX2.5 have been identified in only 3% of patients with sporadic CHTD. Moreover, a survey of monozygotic twins yielded a discordance rate of 92%, suggesting that somatic events, genetic or epigenetic, probably play an important role in the etiology of CHTD. METHODOLOGY/PRINCIPAL FINDINGS: To assess the role of somatic genetic or epigenetic processes in CHTD, we analyzed gene expression, genome-wide methylation, and structural genome variations in normal versus ectopic thyroid tissue. In total, 1011 genes were more than two-fold induced or repressed. Expression array was validated by quantitative real-time RT-PCR for 100 genes. After correction for differences in thyroid activation state, 19 genes were exclusively associated with thyroid ectopy, among which genes involved in embryonic development (e.g. TXNIP) and in the Wnt pathway (e.g. SFRP2 and FRZB) were observed. None of the thyroid related transcription factors (FOXE1, HHEX, NKX2.1, NKX2.5) showed decreased expression, whereas PAX8 expression was associated with thyroid activation state. Finally, the expression profile was independent of promoter and CpG island methylation and of structural genome variations. CONCLUSIONS/SIGNIFICANCE: This is the first integrative molecular analysis of ectopic thyroid tissue. Ectopic thyroids show a differential gene expression compared to that of normal thyroids, although molecular basis could not be defined. Replication of this pilot study on a larger cohort could lead to unraveling the elusive cause of defective thyroid migration during embryogenesis.