ESPE Abstracts (2018) 89 FC5.2

Enrichment of Inherited Rare Variants in Non-Syndromic Congenital Hypothyroidism from Thyroid Dysgenesis Identified By Exome Sequencing: the Contribution of IKBKE to Vasculogenesis and Thyroid Development

Stéphanie Larrivée-Vaniera, Fabien Magnea, Martineau Jean-Louisa, Aurore Carréb, Helen Buic, Mark E. Samuelsa, Michel Polakd, Guy Van Vlieta & Johnny Deladoëya


aDepartment of Pediatrics, Research Center of Centre Hospitalier Universitaire Sainte-Justine, Endocrinology Service, Université de Montréal, Montréal, Canada; bFaculté de Médecine, INSERM U1016, Cochin Institute, Université Paris Descartes, Sorbonne Paris Cité, Paris, France; cEndocrinology Service, Montreal Children Hospital, McGill University, Montreal, Canada; dPediatric Endocrinology, Gynecology and Diabetology Unit, Hôpital Universitaire Necker-Enfants Malades, AP-HP, Paris, France


Congenital hypothyroidism from thyroid dysgenesis (CHTD) is mainly a sporadic and non-syndromic condition occurring in 1:4,500 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,. As this latter possibility was recently proven right in cases of non-syndromic congenital heart defects, we analysed the burden of inherited rare variants in the exome of 30 cases of NS-CHTD compared to that of 495 controls sequenced and analysed on the same platform. Gene-burden analysis identified 19 genes enriched in NS-CHTD, including IKBKE. Three IKBKE rare variants were also identified in an independent cohort of 107 cases of NS-CHTD. IKBKE is a member of the inhibitor of κB kinase (IKK) family. It is implicated in the non-canonical pathway of NF-κB and interferon regulatory factor signalling. Furthermore, it has been associated with inflammation, cell transformation, and progression of many cancers. Functional assays showed that IKBKE depletion decreases migration of Nthy-Ori cells (a human thyroid cell line) in vitro. Moreover, ikbke depletion in zebrafish caused defective aortic arch artery formation and abnormal thyroid morphogenesis. The phenotype was observed in two different ikbke morphants in which the level of ikbke transcripts correlates inversely with the phenotype, suggesting a dose-effect relationship. Moreover, a partial rescue of the migration defect was observed with injection of human IKBKE RNA in ikbke morphants. Our results further expand the growing list of predisposing genes for CHTD and confirm the association between vasculogenesis and congenital thyroid malformations.