ESPE Abstracts (2019) 92 FC5.4

Thyroid Dysgenesis: Exome-Wide Analysis Identifies Rare Variants in Genes Involved in Thyroid Development and Cancer

Stéphanie Larrivée-Vanier1,2, Martineau Jean-Louis1, Fabien Magne1, Helen Bui3, Mark E. Samuels1,4, Michel Polak5, Guy Van Vliet1,6, Johnny Deladoëy1,6,5


1Research Center of Centre Hospitalier Universitaire Sainte-Justine, Montreal, Canada. 2Department of Biochemistry, Université de Montréal, Montreal, Canada. 3McGill University Health Center, Montreal, Canada. 4Department of Medicine, Université de Montréal, Montreal, Canada. 5IMAGINE, Université Paris Descartes, Paris, France. 6Department of Paediatrics, Université de Montréal, Montreal, Canada


Context: Congenital hypothyroidism from thyroid dysgenesis (CHTD) is mainly a sporadic and non-syndromic condition occurring in 1:4,000 live births. In contrast to rare cases of syndromic monogenic CHTD, non-syndromic (NS) CHTD shows low familial recurrence risk (~2%) and low concordance rate between MZ twins, suggesting a two-hit scenario combining post-zygotic events with either a de novo monogenic mutation or incomplete penetrance of polygenic inherited variants. This latter possibility was recently proven right in cases of non-syndromic congenital heart defects.

Objective: To evaluate whether a burden of rare disruptive variants is observed in cases of NS-CHTD.

Methods: We compared the exome of 36 cases of NS-CHTD (33 with ectopy and 3 with athyreosis) to that of 495 controls of French-Canadian ancestry to assess the enrichment of rare variants in NS-CHTD by gene burden analysis. Next, we selected disruptive variants by multiple haploinsufficiency tests. Then, genes expressed in thyroid tissue were prioritized.

Results: Gene-based burden testing showed an enrichment of rare variants in 31 genes in the NS-CHTD cases. On the other hand, multiple haploinsufficiency tests found enrichment of disruptive variants in 15 genes. Based on expression in thyroid tissue, 3 of these 15 genes are either overexpressed in thyroid cancers (ATF5 and FOXK1) or involved in cell migration (PLXNA4).

Conclusions: Our data suggest that: (i) a burden of disruptive variants contributes to the risk of NS-CHTD and (ii) ATF5 and FOXK1 have a divergent function in thyroid development and cancer.

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