title: Targeted Resequencing of 29 Candidate Genes and Mouse Expression Studies Implicate ZIC3 and FOXF1 in Human VATER/VACTERL Association.
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.
authors: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors: Alina C
authors: AC
authors: Hilger
authors: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.|Department of Internal Medicine, Division of Nephrology, University Clinic Leipzig, Leipzig, Germany.
authors: Jan
authors: J
authors: Halbritter
authors: Department of Developmental Genetics, Max-Planck-Institute for Molecular Genetics, Berlin, Germany.|Division of Cancer Biology and Genetics, Queen's University, Kingston, Ontario, Canada.
authors: Tracie
authors: T
authors: Pennimpede
authors: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors: Amelie
authors: A
authors: van der Ven
authors: Department of Neonatology and Pediatric Intensive Care, Children's Hospital, University of Bonn, Bonn, Germany.
authors: Georgia
authors: G
authors: Sarma
authors: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors: Daniela A
authors: DA
authors: Braun
authors: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors: Jonathan D
authors: JD
authors: Porath
authors: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors: Stefan
authors: S
authors: Kohl
authors: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors: Daw-Yang
authors: DY
authors: Hwang
authors: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.
authors: Gabriel C
authors: GC
authors: Dworschak
authors: Department of Developmental Genetics, Max-Planck-Institute for Molecular Genetics, Berlin, Germany.
authors: Bernhard G
authors: BG
authors: Hermann
authors: Institute of Experimental Hematology and Transfusion Medicine, University of Bonn, Bonn, Germany.
authors: Anna
authors: A
authors: Pavlova
authors: Institute of Experimental Hematology and Transfusion Medicine, University of Bonn, Bonn, Germany.|Department of Natural Sciences, Lebanese American University, Byblos/Beirut, Lebanon.
authors: Osman
authors: O
authors: El-Maarri
authors: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.
authors: Markus M
authors: MM
authors: Nöthen
authors: Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany.
authors: Michael
authors: M
authors: Ludwig
authors: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Neonatology and Pediatric Intensive Care, Children's Hospital, University of Bonn, Bonn, Germany.
authors: Heiko
authors: H
authors: Reutter
authors: Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts.|Howard Hughes Medical Institute, Chevy Chase, Maryland.
authors: Friedhelm
authors: F
authors: Hildebrandt
mesh_terms: D000483:Alleles; D001003:Anal Canal / Q000002:abnormalities*; D000818:Animals; D001006:Anus, Imperforate / Q000175:diagnosis / Q000235:genetics*; D002923:Cilia / Q000235:genetics; D019295:Computational Biology / Q000379:methods; D004252:DNA Mutational Analysis; D004947:Esophagus / Q000002:abnormalities*; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D056726:Genetic Association Studies; D005838:Genotype; D006330:Heart Defects, Congenital / Q000175:diagnosis / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007668:Kidney / Q000002:abnormalities*; D017880:Limb Deformities, Congenital / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D051379:Mice; D009154:Mutation; D010641:Phenotype; D011884:Radius / Q000002:abnormalities*; D013131:Spine / Q000002:abnormalities*; D014132:Trachea / Q000002:abnormalities*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: C098521:FOXF1 protein, human; D051858:Forkhead Transcription Factors; C486293:Foxf1 protein, mouse; D018398:Homeodomain Proteins; D014157:Transcription Factors; C491595:ZIC3 protein, human; C491594:Zic3 protein, mouse
keywords: FOXF1; VATER/VACTERL association; ZIC3; cilia