TY  - JOUR
A1  - Zhang, Rong
A1  - Gehlen, Jan
A1  - Kawalia, Amit
A1  - Melissari, Maria-Theodora
A1  - Dakal, Tikam Chand
A1  - Menon, Athira M.
A1  - Höfele, Julia
A1  - Riedhammer, Korbinian
A1  - Waffenschmidt, Lea
A1  - Fabian, Julia
A1  - Breuer, Katinka
A1  - Kalanithy, Jeshurun
A1  - Hilger, Alina Christine
A1  - Sharma, Amit
A1  - Hölscher, Alice
A1  - Boemers, Thomas M.
A1  - Pauly, Markus
A1  - Leutner, Andreas
A1  - Fuchs, Jörg
A1  - Seitz, Guido
A1  - Ludwikowski, Barbara
A1  - Gomez, Barbara
A1  - Hubertus, Jochen
A1  - Heydweiller, Andreas
A1  - Kurz, Ralf
A1  - Leonhardt, Johannes
A1  - Kosch, Ferdinand
A1  - Holland-Cunz, Stefan
A1  - Münsterer, Oliver
A1  - Ure, Beno
A1  - Schmiedeke, Eberhard
A1  - Neser, Jörg
A1  - Degenhardt, Petra
A1  - Märzheuser, Stefanie
A1  - Kleine, Katharina
A1  - Schäfer, Mattias
A1  - Spychalski, Nicole
A1  - Deffaa, Oliver J.
A1  - Gosemann, Jan-Hendrik
A1  - Lacher, Martin
A1  - Heilmann-Heimbach, Stefanie
A1  - Zwink, Nadine
A1  - Jenetzky, Ekkehart
A1  - Ludwig, Michael
A1  - Grote, Phillip
A1  - Schumacher, Johannes
A1  - Thiele, Holger
A1  - Reutter, Heiko
T1  - Human exome and mouse embryonic expression data implicate ZFHX3, TRPS1, and CHD7 in human esophageal atresia
T2  - PLoS one
N2  - 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.
KW  - Computer-aided drug design
KW  - Transcriptome analysis
KW  - Gene expression
KW  - Embryos
KW  - Congenital anomalies
KW  - Mutation databases
KW  - Amino acid analysis
KW  - DNA sequence analysis
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/54935
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-549357
SN  - 1932-6203
N1  - 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.
VL  - 15
IS  - (6): e0234246
SP  - 1
EP  - 14
PB  - PLoS
CY  - Lawrence, Kan.
ER  -