The Genetic Basis of Congenital Hypothyroidism (360G-Wellcome-100585_Z_12_A)

I have already identified 2 novel genetic causal variants for congenital hypothyroidism (CH) by whole exome sequencing (WES); IGSF1 defects in central hypothyroidism and SLC26A7 in dyshormonogenetic CH. I will therefore continue this strategy to identify further genetic causes of CH. I will expand my CH cohort, enriched for probability of genetic mutations. After excluding candidate gene defects, cases will undergo WES. I will then undertake functional characterization of specific novel variant s using in vitro techniques and a zebrafish model of thyroid development. Human SLC26A7 mutations are a novel cause of dyshormonogenetic CH and the disorder or its pathogenesis has not been characterized; I will phenotype cases to define this syndrome in more detail. I will characterize the biological function of SLC26A7 (a key transport protein), by performing electrophysiological studies to define its role as a putative anion transporter in the thyroid. Structure-function relationships in S LC26A7 are poorly understood. I will therefore characterize the properties of naturally-occurring and artificial SLC26A7 mutants to define functional domains in this protein.