@article{d58866853f984180b043c87907eea5bb,
title = "Identification and validation of candidate risk genes in endocytic vesicular trafficking associated with esophageal atresia and tracheoesophageal fistulas",
abstract = "Esophageal atresias/tracheoesophageal fistulas (EA/TEF) are rare congenital anomalies caused by aberrant development of the foregut. Previous studies indicate that rare or de novo genetic variants significantly contribute to EA/TEF risk, and most individuals with EA/TEF do not have pathogenic genetic variants in established risk genes. To identify the genetic contributions to EA/TEF, we performed whole genome sequencing of 185 trios (probands and parents) with EA/TEF, including 59 isolated and 126 complex cases with additional congenital anomalies and/or neurodevelopmental disorders. There was a significant burden of protein-altering de novo coding variants in complex cases (p = 3.3 × 10−4), especially in genes that are intolerant of loss-of-function variants in the population. We performed simulation analysis of pathway enrichment based on background mutation rate and identified a number of pathways related to endocytosis and intracellular trafficking that as a group have a significant burden of protein-altering de novo variants. We assessed 18 variants for disease causality using CRISPR-Cas9 mutagenesis in Xenopus and confirmed 13 with tracheoesophageal phenotypes. Our results implicate disruption of endosome-mediated epithelial remodeling as a potential mechanism of foregut developmental defects. Our results suggest significant genetic heterogeneity of EA/TEF and may have implications for the mechanisms of other rare congenital anomalies.",
keywords = "aerodigestive, congenital anomaly, esophageal atresia, tracheoesophageal fistula, Xenopus",
author = "Guojie Zhong and Priyanka Ahimaz and Edwards, {Nicole A.} and Hagen, {Jacob J.} and Christophe Faure and Qiao Lu and Paul Kingma and William Middlesworth and Julie Khlevner and {El Fiky}, Mahmoud and David Schindel and Elizabeth Fialkowski and Adhish Kashyap and Sophia Forlenza and Kenny, {Alan P.} and Zorn, {Aaron M.} and Yufeng Shen and Chung, {Wendy K.}",
note = "Funding Information: We would like to thank the individuals with EA/TEF and their families who participated in the study and the TOFS UK organization for their support of the study. We thank Patricia Lanzano, Jiangyuan Hu, Liyong Deng, and Charles LeDuc from Columbia University for technical assistance. We would like to thank the study coordinators Gentry Wools (UT-Southwest), Amanda Schreibeis (Cincinnati Children{\textquoteright}s Hospital) and Andrew Mason (Oregon Health and Science University) for their assistance. We also thank Dr. Na Zhu, Dr. Xueya Zhou, and other members of Chung and Shen labs for helpful discussions. The whole genome sequencing data were generated through NIH Gabriella Miller Kids First Pediatric Research Program ( X01HL145692 and X01HD100705 ). Microscopy was performed at the CCHMC Confocal Imaging Core. The work was support by NIH grants P01HD093363 (A.M.Z., Y.S., and W.K.C.), R01GM120609 (G.Z., Y.S.), and R03HL147197 (Y.S.). N.A.E. is supported by a Canadian Institutes of Health Research postdoctoral fellowship. We acknowledge Marko Horb and Danielle Jordan at the National Xenopus Resource for generating sox2 germline mutant Xenopus tadpoles for this study (RRID: SCR_013731 ). Funding Information: We would like to thank the individuals with EA/TEF and their families who participated in the study and the TOFS UK organization for their support of the study. We thank Patricia Lanzano, Jiangyuan Hu, Liyong Deng, and Charles LeDuc from Columbia University for technical assistance. We would like to thank the study coordinators Gentry Wools (UT-Southwest), Amanda Schreibeis (Cincinnati Children's Hospital) and Andrew Mason (Oregon Health and Science University) for their assistance. We also thank Dr. Na Zhu, Dr. Xueya Zhou, and other members of Chung and Shen labs for helpful discussions. The whole genome sequencing data were generated through NIH Gabriella Miller Kids First Pediatric Research Program (X01HL145692 and X01HD100705). Microscopy was performed at the CCHMC Confocal Imaging Core. The work was support by NIH grants P01HD093363 (A.M.Z. Y.S. and W.K.C.), R01GM120609 (G.Z. Y.S.), and R03HL147197 (Y.S.). N.A.E. is supported by a Canadian Institutes of Health Research postdoctoral fellowship. We acknowledge Marko Horb and Danielle Jordan at the National Xenopus Resource for generating sox2 germline mutant Xenopus tadpoles for this study (RRID: SCR_013731). W.K.C. Y.S. and A.M.Z. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: W.K.C. Y.S. and A.M.Z. Acquisition, analysis, or interpretation of data: G.Z. P.A. N.A.E. J.J.H. C.F. P.K. W.M. J.K. M.E.F. D.S. E.F. A.K. S.F. A.P.K. A.M.Z. Y.S. and W.K.C. Drafting of the manuscript: G.Z. P.A. N.A.E. A.M.Z. Y.S. and W.K.C. Critical revision of the manuscript for important intellectual content: G.Z. P.A. N.A.E. J.J.H. C.F. P.K. W.M. J.K. M.E.F. D.S. E.F. A.K. S.F. A.P.K. A.M.Z. Y.S. and W.K.C. Statistical analysis: G.Z. P.A. N.A.E. A.M.Z. and Y.S. Xenopus experimental design: N.A.E. A.K. Xenopus experiment: N.A.E. A.K. S.F. A.P.K. Supervision: A.M.Z. Y.S. and W.K.C. The authors read and approved the final manuscript. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2022 The Author(s)",
year = "2022",
month = jul,
day = "14",
doi = "10.1016/j.xhgg.2022.100107",
language = "English (US)",
volume = "3",
journal = "Human Genetics and Genomics Advances",
issn = "2666-2477",
publisher = "Cell Press",
number = "3",
}