ESPE Abstracts

Background and hypotheses: Congenital hypothyroidism due to thyroid dysgenesis (CHTD) is a disorder with a prevalence of one in 4,000 live births, the cause of which remains unknown. The most common diagnostic category is thyroid ectopy, which occurs in up to 80% of CHTD cases. CHTD is predominantly not inherited and has a high discordance rate (>92%) between monozygotic (MZ) twins. The sporadic nature of CHTD might be explained by somatic events such as autosomal monoallelic expression (AME), given that genes expressed in a monoallelic way are more vulnerable to otherwise benign heterozygous genetic or epigenetic mutations.

Objective: To search for complete (90%) AME in normal and dysgenetic thyroid tissues.

Method: Aggregated analysis of whole-exome and bulk RNA sequencing performed on two ectopic thyroids, four normal thyroids and the human thyroid cell line Nthy-ori.

Results: A median of 5,062 (range 2,081–5,270) genes per sample showed sufficient numbers of heterozygous SNPs to be informative. The median monoallelic expression represented 22 (range 16–32) of the informative genes for each thyroid sample. Examples of genes displaying AME are FCGBP, ZNF331, USP10, BCLAF1 and some HLA genes; these genes are involved in epithelial-mesenchymal transition, cell migration, cancer and immunity.

Conclusion: AME may account for the high discordance rate observed between MZ twins and for the sporadic nature of CHTD. Our findings have also implications for other pathologies including cancers and autoimmune disorders of the thyroid.