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.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology