Targeted Resequencing of 29 Candidate Genes and Mouse Expression Studies Implicate ZIC3 and FOXF1 in Human VATER/VACTERL Association |
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| Authors: | Alina C Hilger Jan Halbritter Tracie Pennimpede Amelie van der Ven Georgia Sarma Daniela A Braun Jonathan D Porath Stefan Kohl Daw‐Yang Hwang Gabriel C Dworschak Bernhard G Hermann Anna Pavlova Osman El‐Maarri Markus M Nöthen Michael Ludwig Heiko Reutter Friedhelm Hildebrandt |
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| Institution: | 1. Institute of Human Genetics, University of Bonn, Bonn, Germany;2. Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts;3. Department of Internal Medicine, Division of Nephrology, University Clinic Leipzig, Leipzig, Germany;4. Department of Developmental Genetics, Max‐Planck‐Institute for Molecular Genetics, Berlin, Germany;5. Division of Cancer Biology and Genetics, Queen's University, Kingston, Ontario, Canada;6. Department of Neonatology and Pediatric Intensive Care, Children's Hospital, University of Bonn, Bonn, Germany;7. Institute of Experimental Hematology and Transfusion Medicine, University of Bonn, Bonn, Germany;8. Department of Natural Sciences, Lebanese American University, Byblos/Beirut, Lebanon;9. Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany;10. Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany;11. Howard Hughes Medical Institute, Chevy Chase, Maryland |
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| Abstract: | The VATER/VACTERL association describes the combination of congenital anomalies including vertebral defects, anorectal malformations, cardiac defects, tracheoesophageal fistula with or without esophageal atresia, renal malformations, and limb defects. As mutations in ciliary genes were observed in diseases related to VATER/VACTERL, we performed targeted resequencing of 25 ciliary candidate genes as well as disease‐associated genes (FOXF1, HOXD13, PTEN, ZIC3) in 123 patients with VATER/VACTERL or VATER/VACTERL‐like phenotype. We detected no biallelic mutation in any of the 25 ciliary candidate genes; however, identified an identical, probably disease‐causing ZIC3 missense mutation (p.Gly17Cys) in four patients and a FOXF1 de novo mutation (p.Gly220Cys) in a further patient. In situ hybridization analyses in mouse embryos between E9.5 and E14.5 revealed Zic3 expression in limb and prevertebral structures, and Foxf1 expression in esophageal, tracheal, vertebral, anal, and genital tubercle tissues, hence VATER/VACTERL organ systems. These data provide strong evidence that mutations in ZIC3 or FOXF1 contribute to VATER/VACTERL. |
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| Keywords: | VATER/VACTERL association cilia ZIC3 FOXF1 |
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