ESPE Abstracts

Background: Congenital hypothyroidism (CH) is referred to dyshormonogenesis for 15 to 30%. Homozygous mutations associated have been demonstrated in DUOX2, TPO, TG, SLC5A5 (NIS), SLC26A4 (Pendred), DUOXA2, and IYD (DEHAL1) genes.

Objective and hypotheses: Previous studies focusing on one or few thyroid-specific genes have proved not to be comprehensive enough for understanding physiopathological mechanisms of HC with dyshormonogenesis. Emerging diagnostic tools as next generation sequencing (NGS) led to efficiently study some targeted genes involved in a specific disease.

Method: Using this approach, we have studied DNA samples from 30 newborns HC and eutopic gland for 18 candidate genes (CDS and UTR) to explore the causative genes for thyroid dyshormonogenesis.

Results: Among the 30 infants, 16 (55%) presented mutation in one or more genes of the thyroid hormone synthesis axis. For 9 infants we have identified homozygous or composite heterozygous mutation for TG, DUOX2, TPO or SLC5A5 genes whereas 5 presented heterozygous mutations in two different genes of the thyroid hormonogenesis pathway, TG and DUOX2 or TG and TPO. In 2 cases, heterozygous mutation in the TG gene was the unique anomaly identified in the hormone synthesis pathway but related to disturbed hormonal balance. Exploring the thyroid hormone synthesis pathway by NGS has revealed that 7/16 newborns (43%) presented composite heterozygous or heterozygous mutation in two genes involved in the hormone synthesis process. Thyroglobulin is the high –frequency mutated gene in our population. In all cases the correlation between biological and imaging studies and molecular status was examined.

Conclusion: The systematic exploration of genes involved in the thyroid hormone synthesis by NGS in HC with eutopic gland showed high level diagnostic relevance. Furthermore significant percentage of them occurs when two steps in the hormone synthesis process are impaired. Heterozygous composite mutations could be related to the phenotypic heterogeneity observed for HC with dyshormonogenesis.