Functional characterization of non-coding variants in disease-causing regions of benign choreoathetosis (CAHTP) and thyroid dysgenesis (CHTD)

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The transcription factor NKX2-1 is a master regulator not only of thyroid follicular cells, but also of specific neuronal cell types in the ventral telencephalon, the diencephalon, and of pulmonary alveolar epithelial cells. Mutations of the NKX2-1 gene cause benign choreoathetosis and congenital hypothyroidism with or without pulmonary dysfunction (CAHTP, OMIM #610978), an autosomal dominant disorder with variable penetrance and severity of thyroid and pulmonary phenotypes; as initially shown by our group already in 2002. During the first funding period we used WGS to identify non-coding variants in the NKX2-1 gene locus of a cohort of CAHTP patients with an intact NKX2-1 gene. By analyzing epigenomic signatures of the NKX2-1 gene locus, we assigned a putative 100 kb disease-associated region at 14q13 downstream of the NKX2-1 gene. In the first part of this project, we will target this region with different techniques to examine the cis-regulatory role of this genomic region and to analyze the impact of the non-coding variants detected by WGS in our cohort of 25 CAHTP index patients. To gain additional insights into the genetic mechanisms of thyroid dysgenesis (CHTD), we conducted a collaborative genome-wide association study (GWAS) with Satoshi Narumi from Keio University School of Medicine, Tokyo (Japan) and identified a first disease-associated region for CHTD in a non-coding genomic region at 2q33.3. The significant top genotyped SNP (rs9789446) was located in a 72 kb intronic region that contains cis-regulatory sequences for FZD5 and CCNYL1 expression in thyroid tissue as inferred from a combination of epigenome, transcriptome, and chromatin interaction data sets. To begin to formally demonstrate the disease relevance of this non-coding region for thyroid dysgenesis, we will characterize the activity of putative of cis-regulatory elements at 2q33.3 in the second funding period of this project.