ESPE Abstracts

Background: Congenital hypothyroidism (CH) affects one in 3000 children at birth. In 65% of cases, CH is due to thyroid dysgenesis (CHDT). For CHDT, there is a family component and therefore genetic. Over the past 20 years, disease-causing mutations in 10 genes have been implicated in CHDT cases (NKX2-1/TTF1, FOXE1/TTF2, NKX2-5, PAX8, GLIS3, NTN1/Netrin-1, JAG1, BOREALIN/CDCA8, TUBB1 and TSHR). In the vast majority of cases, the inheritance model is autosomal dominant. However, less than 10% of all CHDT patients have a mutation in one of these genes. Except for the 10 genes above, in our knowledge, other genes are involved in the development of the thyroid in mice, zebrafish or in vitro, which prompted us to explore genetic aspects of these genes in humans.

Aim of the study: To perform both a genetic inventory and genes interactions of all the known genes involved in the thyroid development by searching for molecular variants of these genes in a group of patients with a very well-described CHDT.

Methods: Patients were recruited through HYPOTYGEN Programme Hospitalier de Recherche Clinique (PHRC). HYPOTYGEN study is a multi-center cross-sectional clinical trial which aims to describe the population with CHDT. 482 patients with CHDT were collected and DNA samples from more than 318 CHDT patients have been sequenced through a custom-targeted NGS panel (n = 79), which were compared with 709 controls. Then, statistical analysis were performed to compare these two groups.

Results: We confirmed that patients with CHDT have a disease-causing mutation in one of the 10 known genes in 7.9% of cases. By comparing the sequencing results in the group of CHDT patients versus controls, we found variants in genes involved in the development of the thyroid, not yet involved in humans, i.e. EDN1, EYA1, CHRD, ISL1. However, the results are more complex than expected. We found, in a very interesting way, an oligogenism in the CHDT cohort as compared to the controls (P < 0.01). CHDT have a more complex origin than that described so far and the accumulation of our knowledge allows us to refine the genetic diagnosis of CHDT.

Conclusion: Beyond the monogenic model, we found an oligogenic one that explain 6,2% of the CHDT patients. The main challenge in the next years will be to enhance our understanding in the pathogenesis of CHDT by using a new paradigm, the oligogenism model on known genes.

Supported in part by a PHRC, ClinicalTrials.gov NCT01916018, Sandoz SAS, Merck