title: Copy number variations in 375 patients with oesophageal atresia and/or tracheoesophageal fistula.
abstract: Oesophageal atresia (OA) with or without tracheoesophageal fistula (TOF) are rare anatomical congenital malformations whose cause is unknown in over 90% of patients. A genetic background is suggested, and among the reported genetic defects are copy number variations (CNVs). We hypothesized that CNVs contribute to OA/TOF development. Quantifying their prevalence could aid in genetic diagnosis and clinical care strategies. Therefore, we profiled 375 patients in a combined Dutch, American and German cohort via genomic microarray and compared the CNV profiles with their unaffected parents and published control cohorts. We identified 167 rare CNVs containing genes (frequency<0.0005 in our in-house cohort). Eight rare CNVs - in six patients - were de novo, including one CNV previously associated with oesophageal disease. (hg19 chr7:g.(143820444_143839360)_(159119486_159138663)del) 1.55% of isolated OA/TOF patients and 1.62% of patients with additional congenital anomalies had de novo CNVs. Furthermore, three (15q13.3, 16p13.3 and 22q11.2) susceptibility loci were identified based on their overlap with known OA/TOF-associated CNV syndromes and overlap with loci in published CNV association case-control studies in developmental delay. Our study suggests that CNVs contribute to OA/TOF development. In addition to the identified likely deleterious de novo CNVs, we detected 167 rare CNVs. Although not directly disease-causing, these CNVs might be of interest, as they can act as a modifier in a multiple hit model, or as the second hit in a recessive condition.
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands.|Department of Paediatric Surgery, Erasmus Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Erwin
authors.identifier: 0000-0001-8235-4010
authors.initials: E
authors.lastname: Brosens
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Marsch
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands.|Department of Paediatric Surgery, Erasmus Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: de Jong
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.|Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Hitisha P
authors.initials: HP
authors.lastname: Zaveri
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Alina C
authors.initials: AC
authors.lastname: Hilger
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Vera Gisela
authors.initials: VG
authors.lastname: Choinitzki
authors.affiliation: Department of Paediatric Surgery and Urology, Children's Hospital of Cologne, Cologne, Germany.
authors.forename: Alice
authors.initials: A
authors.lastname: Hölscher
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Human Genomics Research Group, Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland.
authors.forename: Per
authors.identifier: 0000-0002-6573-983X
authors.initials: P
authors.lastname: Hoffmann
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Human Genomics Research Group, Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Herms
authors.affiliation: Department of Paediatric Surgery and Urology, Children's Hospital of Cologne, Cologne, Germany.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Boemers
authors.affiliation: Center of Paediatric Surgery Hannover, Hannover Medical School and Bult Children's Hospital, Hannover, Germany.
authors.forename: Benno M
authors.initials: BM
authors.lastname: Ure
authors.affiliation: Center of Paediatric Surgery Hannover, Hannover Medical School and Bult Children's Hospital, Hannover, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Lacher
authors.affiliation: Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Ludwig
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Bert H
authors.initials: BH
authors.lastname: Eussen
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Robert M
authors.initials: RM
authors.lastname: van der Helm
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Hannie
authors.initials: H
authors.lastname: Douben
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Diane
authors.initials: D
authors.lastname: Van Opstal
authors.affiliation: Department of Paediatric Surgery, Erasmus Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Rene M H
authors.initials: RM
authors.lastname: Wijnen
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: H Berna
authors.initials: HB
authors.lastname: Beverloo
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Yolande
authors.initials: Y
authors.lastname: van Bever
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Alice S
authors.initials: AS
authors.lastname: Brooks
authors.affiliation: Department of Paediatric Surgery, Erasmus Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Hanneke
authors.initials: H
authors.lastname: IJsselstijn
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.|Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Daryl A
authors.initials: DA
authors.lastname: Scott
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Schumacher
authors.affiliation: Department of Paediatric Surgery, Erasmus Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Dick
authors.initials: D
authors.lastname: Tibboel
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany.|Department of Neonatology and Paediatric Intensive Care, University of Bonn, Bonn, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Reutter
authors.affiliation: Department of Clinical Genetics, Erasmus Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: Annelies
authors.initials: A
authors.lastname: de Klein
mesh_terms: D000328:Adult; D002648:Child; D056915:DNA Copy Number Variations; D004933:Esophageal Atresia / Q000235:genetics*; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans; D014138:Tracheoesophageal Fistula / Q000235:genetics*