Copy number variations in 375 patients with oesophageal atresia and/or tracheoesophageal fistula.

Autor: Brosens E; 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., Marsch F; Institute of Human Genetics, University of Bonn, Bonn, Germany., de Jong EM; 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., Zaveri HP; 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., Hilger AC; Institute of Human Genetics, University of Bonn, Bonn, Germany., Choinitzki VG; Institute of Human Genetics, University of Bonn, Bonn, Germany., Hölscher A; Department of Paediatric Surgery and Urology, Children's Hospital of Cologne, Cologne, Germany., Hoffmann P; Institute of Human Genetics, University of Bonn, Bonn, Germany.; Human Genomics Research Group, Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland., Herms S; Institute of Human Genetics, University of Bonn, Bonn, Germany.; Human Genomics Research Group, Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland., Boemers TM; Department of Paediatric Surgery and Urology, Children's Hospital of Cologne, Cologne, Germany., Ure BM; Center of Paediatric Surgery Hannover, Hannover Medical School and Bult Children's Hospital, Hannover, Germany., Lacher M; Center of Paediatric Surgery Hannover, Hannover Medical School and Bult Children's Hospital, Hannover, Germany., Ludwig M; Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany., Eussen BH; Department of Clinical Genetics, Erasmus Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands., van der Helm RM; Department of Clinical Genetics, Erasmus Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands., Douben H; Department of Clinical Genetics, Erasmus Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands., Van Opstal D; Department of Clinical Genetics, Erasmus Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands., Wijnen RM; Department of Paediatric Surgery, Erasmus Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands., Beverloo HB; Department of Clinical Genetics, Erasmus Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands., van Bever Y; Department of Clinical Genetics, Erasmus Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands., Brooks AS; Department of Clinical Genetics, Erasmus Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands., IJsselstijn H; Department of Paediatric Surgery, Erasmus Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands., Scott DA; 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., Schumacher J; Institute of Human Genetics, University of Bonn, Bonn, Germany., Tibboel D; Department of Paediatric Surgery, Erasmus Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands., Reutter H; Institute of Human Genetics, University of Bonn, Bonn, Germany.; Department of Neonatology and Paediatric Intensive Care, University of Bonn, Bonn, Germany., de Klein A; Department of Clinical Genetics, Erasmus Medical Centre - Sophia Children's Hospital, Rotterdam, The Netherlands.
Jazyk: angličtina
Zdroj: European journal of human genetics : EJHG [Eur J Hum Genet] 2016 Dec; Vol. 24 (12), pp. 1715-1723. Date of Electronic Publication: 2016 Jul 20.
DOI: 10.1038/ejhg.2016.86
Abstrakt: 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.
Databáze: MEDLINE
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