Human exome and mouse embryonic expression data implicate ZFHX3, TRPS1, and CHD7 in human esophageal atresia
Year: 2020
Type: article
Study design: Observational Study
Abstract: 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.
Source: PLoS ONE
Authors: Rong Zhang, Jan Gehlen, Amit Kawalia, Maria-Theodora Melissari, Tikam Chand Dakal, Athira M. Menon, Julia Höfele, Korbinian Riedhammer, Lea Waffenschmidt, Julia Fabian, Katinka Breuer, Jeshurun Kalanithy, Alina Christine Hilger, Amit Sharma, Alice Hölscher, Thomas M. Boemers, Markus Pauly, Andreas Leutner, Jörg Fuchs, Guido Seitz, Barbara M. Ludwikowski, Barbara Gomez, Jochen Hubertus, Andreas Heydweiller, Ralf Kurz, Johannes Leonhardt, Ferdinand Kosch, Stefan Holland-Cunz, Oliver Münsterer, Beno Ure, Eberhard Schmiedeke, Jörg Neser, Petra Degenhardt, Stefanie Märzheuser, Katharina Kleine, Mattias Schäfer, Nicole Spychalski, Oliver J. Deffaa, Jan-Hendrik Gosemann, Martin Lacher, Stefanie Heilmann-Heimbach, Nadine Zwink, Ekkehart Jenetzky, Michael Ludwig, Phillip Grote, Johannes Schumacher, Holger Thiele, Heiko Reutter
Institutions: University of Bonn, Universitätsklinikum Gießen und Marburg, University of Cologne, Goethe University Frankfurt, Mohanlal Sukhadia University, TUM Klinikum, Institut für Humangenetik, Technical University of Munich, University Hospital Bonn, University Hospital Cologne, Asklepios Klinik Sankt Augustin, Asklepios, Klinikum Dortmund, University Children's Hospital Tübingen, University of Tübingen, Philipps University of Marburg, Kinderkrankenhaus auf der Bult, Ludwig-Maximilians-Universität München, Klinikum Braunschweig, Städtisches Klinikum Karlsruhe, University Children’s Hospital Basel, Johannes Gutenberg University Mainz, University Medical Center of the Johannes Gutenberg University Mainz, Medizinische Hochschule Hannover, Klinikum Bremen-Mitte, Klinikum Chemnitz, Klinikum Ernst von Bergmann, Charité – Universitätsmedizin Berlin, Evangelisches Krankenhaus Oberhausen, Cnopf´sche Kinderklinik, Leipzig University, Witten/Herdecke University
Language: English
Topic: Esophageal and GI Pathology
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $1,695
OpenAlex ID: W3033999998