Human exome and mouse embryonic expression data implicate ZFHX3, TRPS1, and CHD7 in human esophageal atresia.

Autor: Zhang R; Institute of Human Genetics, Medical Faculty of Bonn, University of Bonn, Bonn, Germany., Gehlen J; Institute of Human Genetics, University Hospital of Marburg, Marburg, Germany., Kawalia A; Cologne Center for Genomics, University of Cologne, Cologne, Germany., Melissari MT; Institute of Cardiovascular Regeneration, Center for Molecular Medicine, University of Frankfurt, Frankfurt am Main, Germany., Dakal TC; Department of Biotechnology, Mohanlal Sukhadia University Udaipur, Rajasthan, India., Menon AM; Department of Biotechnology, Mohanlal Sukhadia University Udaipur, Rajasthan, India., Höfele J; Institute of Human Genetics, Klinikum Rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany., Riedhammer K; Institute of Human Genetics, Klinikum Rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany.; Department of Nephrology, Klinikum Rechts der Isar, Technical University of Munich, School of Medicine, Munich, Germany., Waffenschmidt L; Institute of Human Genetics, Medical Faculty of Bonn, University of Bonn, Bonn, Germany., Fabian J; Institute of Human Genetics, Medical Faculty of Bonn, University of Bonn, Bonn, Germany., Breuer K; Institute of Human Genetics, Medical Faculty of Bonn, University of Bonn, Bonn, Germany., Kalanithy J; Institute of Human Genetics, Medical Faculty of Bonn, University of Bonn, Bonn, Germany., Hilger AC; Department of Pediatrics, Clinic for Pediatrics, University Hospital Bonn, Bonn, Germany., Sharma A; Department of Neurology, University Hospital Bonn, Bonn, Germany.; Department of Ophthalmology, University Hospital Bonn, Bonn, Germany., Hölscher A; Department of Pediatric Surgery and Urology, University Hospital Cologne, Cologne, Germany., Boemers TM; Department of Pediatric Surgery and Urology, University Hospital Cologne, Cologne, Germany., Pauly M; Department of Pediatric Surgery, Asklepios Children's Hospital St. Augustin, St. Augustin, Germany., Leutner A; Department of Pediatric Surgery, Medical Center Dortmund, Dortmund, Germany., Fuchs J; Department of Pediatric Surgery Children's Hospital, University of Tübingen, Tübingen, Germany., Seitz G; Department of Pediatric Surgery, University of Marburg, Marburg, Germany., Ludwikowski BM; Department of Pediatric Surgery and Pediatric Urology, Medical Center for Children and Adolescents AUF DER BULT, Hannover, Germany., Gomez B; Department of Pediatric Surgery and Pediatric Urology, Medical Center for Children and Adolescents AUF DER BULT, Hannover, Germany., Hubertus J; Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University, Munich, Germany., Heydweiller A; Department of Pediatric Surgery, University Hospital Bonn, Bonn, Germany., Kurz R; Department of Pediatric Surgery, University Hospital Bonn, Bonn, Germany., Leonhardt J; Department of Pediatric Surgery, Children's Hospital Braunschweig, Braunschweig, Germany., Kosch F; Department of Pediatric Surgery, Städtisches Klinikum Karlsruhe, Karlsruhe, Germany., Holland-Cunz S; Department of Pediatric Surgery, University Children's Hospital Basel (UKBB), Basel, Switzerland., Münsterer O; Department of Pediatric Surgery, University Medicine Mainz, Mainz, Germany., Ure B; Center of Pediatric Surgery Hannover, Hannover Medical School, Hannover, Germany., Schmiedeke E; Clinic for Paediatric Surgery and Paediatric Urology, Klinikum Bremen-Mitte, Bremen, Germany., Neser J; Department of Pediatric Surgery, General Hospital, Chemnitz, Germany., Degenhardt P; Department of Pediatric Surgery, Ernst von Bergmann Hospital, Potsdam, Germany., Märzheuser S; Department of Pediatric Surgery, Campus Virchow Clinic, Charité University Hospital Berlin, Berlin, Germany., Kleine K; Department of Pediatric Surgery, Evangelisches Krankenhaus Oberhausen, Germany., Schäfer M; Department of Pediatric Surgery and Urology, Cnopf'sche Kinderklinik, Nürnberg, Germany., Spychalski N; Department of Pediatric Surgery and Urology, Cnopf'sche Kinderklinik, Nürnberg, Germany., Deffaa OJ; Department of Pediatric Surgery, University of Leipzig, Leipzig, Germany., Gosemann JH; Department of Pediatric Surgery, University of Leipzig, Leipzig, Germany., Lacher M; Department of Pediatric Surgery, University of Leipzig, Leipzig, Germany., Heilmann-Heimbach S; Institute of Human Genetics, Medical Faculty of Bonn, University of Bonn, Bonn, Germany.; Department of Genomics, Life &Brain Center, University of Bonn, Bonn, Germany., Zwink N; Department of Child and Adolescent Psychiatry and Psychotherapy, Johannes-Gutenberg University, Mainz, Germany., Jenetzky E; Department of Child and Adolescent Psychiatry and Psychotherapy, Johannes-Gutenberg University, Mainz, Germany.; Institute of Integrative Medicine, Witten/Herdecke University, Herdecke, Germany., Ludwig M; Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany., Grote P; Institute of Cardiovascular Regeneration, Center for Molecular Medicine, University of Frankfurt, Frankfurt am Main, Germany., Schumacher J; Institute of Human Genetics, Medical Faculty of Bonn, University of Bonn, Bonn, Germany.; Institute of Human Genetics, University Hospital of Marburg, Marburg, Germany., Thiele H; Cologne Center for Genomics, University of Cologne, Cologne, Germany., Reutter H; Institute of Human Genetics, Medical Faculty of Bonn, University of Bonn, Bonn, Germany.; Section of Neonatology and Pediatric Intensive Care, Clinic for Pediatrics, University Hospital Bonn, Bonn, Germany.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2020 Jun 05; Vol. 15 (6), pp. e0234246. Date of Electronic Publication: 2020 Jun 05 (Print Publication: 2020).
DOI: 10.1371/journal.pone.0234246
Abstrakt: Introduction: Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) occurs approximately 1 in 3.500 live births representing the most common malformation of the upper digestive tract. Only half a century ago, EA/TEF was fatal among affected newborns suggesting that the steady birth prevalence might in parts be due to mutational de novo events in genes involved in foregut development.
Methods: To identify mutational de novo events in EA/TEF patients, we surveyed the exome of 30 case-parent trios. Identified and confirmed de novo variants were prioritized using in silico prediction tools. To investigate the embryonic role of genes harboring prioritized de novo variants we performed targeted analysis of mouse transcriptome data of esophageal tissue obtained at the embryonic day (E) E8.5, E12.5, and postnatal.
Results: In total we prioritized 14 novel de novo variants in 14 different genes (APOL2, EEF1D, CHD7, FANCB, GGT6, KIAA0556, NFX1, NPR2, PIGC, SLC5A2, TANC2, TRPS1, UBA3, and ZFHX3) and eight rare de novo variants in eight additional genes (CELSR1, CLP1, GPR133, HPS3, MTA3, PLEC, STAB1, and PPIP5K2). Through personal communication during the project, we identified an additional EA/TEF case-parent trio with a rare de novo variant in ZFHX3. In silico prediction analysis of the identified variants and comparative analysis of mouse transcriptome data of esophageal tissue obtained at E8.5, E12.5, and postnatal prioritized CHD7, TRPS1, and ZFHX3 as EA/TEF candidate genes. Re-sequencing of ZFHX3 in additional 192 EA/TEF patients did not identify further putative EA/TEF-associated variants.
Conclusion: Our study suggests that rare mutational de novo events in genes involved in foregut development contribute to the development of EA/TEF.
Competing Interests: The authors have declared that no competing interests exist.
Databáze: MEDLINE
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