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

  • 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.
Author:Rong Zhang, Jan Gehlen, Amit Kawalia, Maria-Theodora MelissariORCiD, Tikam Chand Dakal, Athira M. Menon, Julia Höfele, Korbinian RiedhammerORCiD, Lea Waffenschmidt, Julia Fabian, Katinka Breuer, Jeshurun Kalanithy, Alina Christine HilgerORCiDGND, Amit SharmaORCiDGND, Alice Hölscher, Thomas M. Boemers, Markus Pauly, Andreas Leutner, Jörg FuchsGND, Guido Seitz, Barbara LudwikowskiORCiD, Barbara Gomez, Jochen HubertusORCiDGND, Andreas Heydweiller, Ralf Kurz, Johannes LeonhardtGND, 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-HeimbachORCiDGND, Nadine Zwink, Ekkehart JenetzkyORCiDGND, Michael Ludwig, Phillip GroteORCiD, Johannes Schumacher, Holger ThieleORCiD, Heiko ReutterORCiDGND
Pubmed Id:
Parent Title (English):PLoS one
Place of publication:Lawrence, Kan.
Contributor(s):Regie Lyn Pastor Santos-Cortez
Document Type:Article
Date of Publication (online):2020/05/05
Date of first Publication:2020/05/05
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2020/06/10
Tag:Amino acid analysis; Computer-aided drug design; Congenital anomalies; DNA sequence analysis; Embryos; Gene expression; Mutation databases; Transcriptome analysis
Issue:(6): e0234246
Page Number:14
First Page:1
Last Page:14
Copyright: © 2020 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0