Identification of Human Craniofacial, Thyroid and Heart Enhancers at the FOXE1 Locus. A. C. Lidral1, S. A. Bullard2, R. A. Cornell3, G. Bonde3, A. Visel5, L. M. Moreno1, J. Machida4, B. Amendt3, M. L. Marazita6 1) Dept Orthodontics, Univ Iowa, Iowa City, IA; 2) Department of Endocrinology, University of Iowa, Iowa City, USA; 3) Department of Anatomy, University of Iowa, Iowa City, USA; 4) Department of Oral and Maxillofacial Surgery, Toyota Memorial Hospital, Toyota City, Aichi, Japan; 5) Genomics Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA. Department of Energy Joint Genome Institute, Walnut Creek, CA, USA; 6) Department of Oral Biology, School of Dental Medicine; Department of Human Genetics, Graduate School of Public Health; Department of Psychiatry, School of Medicine - University of Pittsburgh, Pittsburgh, PA, USA.

   Mutations in FOXE1 cause the congenital Bamforth-Lazarus syndrome comprised of agenesis or dysgenesis of the thyroid, cleft palate and hair anomalies. Three common diseases, isolated cleft lip and cleft palate, hypothyroidism and thyroid cancer have all been mapped to the FOXE1 locus at 9q22.33. However, very few coding mutations have been found, suggesting that the common risk alleles reside in nearby regulatory elements that have yet to be identified. Using a combination of zebrafish and mouse transgenesis, we screened 15 conserved non-coding sequences for enhancer activity, identifying 3 that regulate expression in a tissue specific pattern consistent with endogenous foxe1 expression. These 3, located -82.4 and -67.7 upstream of FOXE1 and another 22.6 kb downstream, are all active in the developing jaws and branchial arches. Two of these, -67.7 and +22.6 are also active in the heart. The -67.7 enhancer also directs expression in the developing thyroid and contains the SNP rs7850258 that is the most significantly associated marker at this locus with both hypothyroidism and thyroid cancer based on genome-wide association studies. Studies to evaluate the functional effects of rs7850258 are ongoing. Our previous studies of isolated cleft lip and cleft palate have indicated the presence of three different FOXE1 risk haplotypes, two of which correspond with the -67.7 and +22.6 enhancers. Given that thyroid diseases and orofacial clefting map to the same locus and that biological function for the affected tissues converge on one enhancer, there may a shared risk for both diseases within families or a population. To this end we evaluated the frequency of thyroid diseases amongst pedigrees segregating for CLP. Personal and family history of thyroid cancer and other thyroid conditions was obtained from case and control families from the Pittsburgh Orofacial Cleft Study (MLM). Interestingly, significantly more case families (27.4%; 248/905) reported history of any thyroid condition than control families ( 19.66%; 163/829; p-value=0.0002). Focusing on thyroid cancer alone, while there was a greater frequency in cleft families (2.89%) than control (2.43%), the difference was not significant (p=0.64). In conclusion, we have demonstrated there are genetic, biological and clinical links between orofacial clefting and thyroid disease at the FOXE1 locus.

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