Open AccessHuman exome and mouse embryonic expression data implicate ZFHX3, TRPS1, and CHD7 in human esophageal atresia
Author(s) -
Rong Zhang,
Jan Gehlen,
Amit Kawalia,
Maria-Theodora Melissari,
Tikam Chand Dakal,
Athira M. Me,
Julia Höfele,
Korbinian Riedhammer,
Lea Waffenschmidt,
Júlia Fabian,
Katinka Breuer,
Jeshurun Kalanithy,
Alina C. Hilger,
Ingo G. H. SchmidtWolf,
A. Hölscher,
Thomas M. Boemers,
Markus Pauly,
Andreas Leutner,
Jörg Fuchs,
Guido Seitz,
Barbara Ludwikowski,
Bárbara Gómez,
Jochen Hubertus,
Andreas Heydweiller,
Ralf Kurz,
Johannes Leonhardt,
Ferdinand Kosch,
Stefan HollandCunz,
Oliver Münsterer,
B. M. Ure,
Eberhard Schmiedeke,
Jörg Neser,
P. Degenhardt,
Stefanie Märzheuser,
Katharina Kleine,
Mattias Schäfer,
Nicole Spychalski,
Oliver Johannes Deffaa,
JanHendrik Gosemann,
Martin Lacher,
Stefanie HeilmannHeimbach,
Nadine Zwink,
Ekkehart Jenetzky,
Michael Ludwig,
Phillip Grote,
Johannes Schumacher,
Holger Thiele,
Heiko Reutter
Publication year - 2020
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0234246
Subject(s) - biology , exome sequencing , in silico , atresia , transcriptome , foregut , tracheoesophageal fistula , genetics , gene , anatomy , gene expression , mutation
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.